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The ESC Textbook of
Vascular Biology
European Society of Cardiology publications
The ESC Textbook of Cardiovascular Medicine (Second Edition)
Edited by A. John Camm, Thomas F. Lüscher, and Patrick W. Serruys

The ESC Textbook of Intensive and Acute Cardiovascular Care (Section Edition)
Edited by Marco Tubaro, Pascal Vranckx, Susanna Price, and Christiaan Vrints

The ESC Textbook of Cardiovascular Imaging (Second Edition)

Edited by José Luis Zamorano, Jeroen Bax, Juhani Knuuti, Udo Sechtem, Patrizio
Lancellotti, and Luigi Badano

The ESC Textbook of Preventive Cardiology

Edited by Stephan Gielen, Guy De Backer, Massimo F. Piepoli, and David Wood

The EHRA Book of Pacemaker, ICD, and CRT Troubleshooting: Case-based learning
with multiple choice questions
Edited by Harran Burri, Carsten Israel, and Jean-Claude Deharo

The EACVI Echo Handbook

Edited by Patrizio Lancellotti and Bernard Cosyns

The ESC Handbook of Preventive Cardiology: Putting prevention into practice

Edited by Catriona Jennings, Ian Graham, and Stephan Gielen

The EACVI Textbook of Echocardiography (Second Edition)

Edited by Patrizio Lancellotti, José Luis Zamorano, Gilbert Habib, and Luigi Badano

The EHRA Book of Interventional Electrophysiology: Case-based learning with mul-

tiple choice questions
Edited by Hein Heidbuchel, Mattias Duytschaever, and Haran Burri

The ESC Textbook of Vascular Biology

Edited by Robert Krams and Magnus Bäck

Forthcoming
The ESC Textbook of Cardiovascular Development
Edited by Jose Maria Perez Pomares and Robert Kelly

The ESC Textbook of Cardiovascular Magnetic Resonance

Edited by Sven Plein, Massimo Lombardi, Steffen Petersen, Emanuela Valsangiacomo,
Chiara Bucciarelli-Ducci, and Victor Ferrari
The ESC Textbook of
Vascular Biology
Edited by

Robert Krams
Faculty of Engineering, Department of Bioengineering, Imperial
College, London, UK

Magnus Bäck
Department of Cardiology, Karolinska University Hospital,
Stockholm, Sweden

1
3
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 Foreword

The legacy and prospects of vascular Atherosclerosis

The role of blood vessels in disease processes was unknown
biology for centuries. The first description of abnormal blood ves-
sels in a patient with coronary disease was provided by
The discovery of circulation Edward Jenner, who later introduced pox vaccination: on 16
October 1793, the then well-known surgeon John Hunter
Blood vessels have been known for centuries, but only
succumbed to a sudden death during an angina attack trig-
William Harvey put them in the right order. Indeed, in his
gered by a dispute over a controversial issue in the board
seminal work Exercitatio anatomica de motu cordis et san-
of St. Georges Hospital. Edward Jenner immediately per-
guinis in animalibus published in 1628 (1), he described
formed an autopsy on his colleague and concluded ‘I found
the motion of the heart and blood in a completely novel
no material disease of the heart, except that the coronary
manner. For the first time he proposed, and provided sup-
artery appeared thickened’ (3). He was not aware that he
porting data for, the circulatory nature of the blood in the
had thereby first described coronary athersclerosis in a
human body. He distinguished arteries and veins based on
patient with a fatal myocardial infarction, a term later used
their function and structure. He had no proof yet of their
by Rudolf Virchow (1821–1902), the leading pathologist
connective structures—the microcirculation—but he dem-
of the 19th century, who said ‘Atherosclerosis is a chronic
onstrated that blood injected into arteries shows up in the
inflammation induced by cholesterol’ (4). It took more than
corresponding veins. Also, he further demonstrated that
a century to prove this bold hypothesis. At first a seminal
the blood circulated under pulsatile pressure and that the
experiment by Nikolay Nikolaevich Anichkov substantiated
amount of blood was finite. It took more than 100 years
the cholesterol hypothesis. Anitschkov (who won the Stalin
until blood pressure and its changes in systole and diastole
and not the Nobel Prize, since he worked in Russia during
was directly measured (2): Stephen Hales performed this
the Soviet era) proved that atherosclerotic plaques can be
crucial experiment in 1733 in a conscious horse using a
induced in the rabbit aorta by a high fat diet (5)—one of the
glass cannula inserted into the femoral artery—an experi-
first contributions to vascular biology!
ment that would not pass any review board today, but made
history.
However, how the circulation might be regulated
Translation of the cholesterol hypothesis
remained unclear for many centuries after Harvey’s work, It is the vision of vascular biology, a term that only evolved
but over time the sympathetic nervous system, the adrenal during recent decades, to stimulate translational research
glands and the role of the kidneys, the renin angiotensin sys- from bench to bedside (Fig. P.1)—obviously this road was
tem and, eventually, natriuretic peptides were discovered. at times very bumpy, but eventually opened new avenues for
Today we do have a reasonable understanding of cardio- patient care (6). In a sense, this is what the Framingham Heart
vascular regulation and the role of the vasculature in this Study did (initiated by the then National Heart Institute in
context, although unknown mediators are continuously the United States). Indeed, the Framingham Heart Study
being discovered. confirmed Anichkov’s observations of rabbits in humans,
vi 
foreword

Oswald Avery and Maclyn McCarty described CRP as an

Clinical ‘acute-phase reactant’ that was increased in the serum of
Patient population
epidemiology patients suffering from a spectrum of inflammatory stim-
uli. In 1943 Gunnar Löfström, from the State Bacteriologic
Patient oriented Laboratory in Stockholm, for the first time suggested that
Individual patient
research CRP might be linked to atherothrombosis—a visionary
thought that attracted little attention of his colleagues. In
the mid-1950s, Irving Kroop and others reported that CRP
Pathophysiology Organ concentrations are indeed increased after a myocardial
infarction. In the mid-1980s, John Volanakis, Mark Pepys,
Physiology Irving Kushner, identified CRP as a hepatically-derived,
Biochemistry Tissue
nonglycosylated, circulating pentraxin composed of 5 iden-
Pharmacology
tical subunits arranged with pentameric symmetry.
Cell biology Cell Despite these early observations, interest in CRP did not
re-emerge until the 1980s when Frederick de Beer, Brad
Berk, and Wayne Alexander described increased CRP con-
centrations among patients with coronary artery disease.
Molecular biology Gene Attilio Maseri and coworkers then found increased levels of
CRP in patients with unstable angina and linked its concen-
trations to clinical outcome (15). The breakthrough came
Fig. P.1╇ The translational nature of vascular biology.
in 1997 with the publication of a prospective evaluation of
CRP in the Physicians Health Study in which baseline CRP
concentrations were higher among those who subsequently
and established that cholesterol, together with blood pres-
went on to have myocardial infarction or stroke than
sure and diabetes, as the prime cardiovascular risk factors
among those who did not (16). The Jupiter Trial, focusing
accounting tor myocardial infarction, stroke and premature
on the effects of rosuvastatin in patients with elevated CRP,
death (7).
further suggested that anti-inflammatory effects of statins
As is typical for modern science, this in turn stimulated
might contribute to the vascular protective effects of the
vascular biologists to elucidate the mechanisms involved
drugs (17).
in atherosclerosis. While Michael S. Brown and Joseph L.
Goldstein characterized the regulation of lipid metabo-
lisms and LDL-receptors and recieved the Nobel Prize for Inflammasome and interleukins
their discoveries in 1985 (8). Others, such as Russel Ross, Science moved again in both directions: from bench to bed-
described the role of growth factors in atherosclerosis (9) side and back again. At first, these clinical data stimulated
and Paul M. Vanhoutte and his fellows (10) delineated the basic research: soon the role of inflammasomes and that of
role of the endothelium in cardiovascular disease. The dis- the interleukin-1β and interleukin-6 pathway were char-
covery of inflammatory cells in atherosclerotic plaques by acterized in mouse models and later also in patients with
Göran Hansson (11) and Peter Libby (12), as well as that of coronary artery disease and acute coronary syndromes
inflammatory markers in patients with coronary disease, (18,19). However, proof is still lacking that these path-
revived Rudolf Virchow’s hypothesis and stimulated vascu- ways—similar to experimental models—is also causally
lar biology as a research field immensely. Daniel Steinberg related to coronary artery disease and acute coronary syn-
provided an important link by showing that particularly dromes and their clinical course in patients. To that end the
oxidized LDL-cholesterol was the culprit as an antigen and CANTOS trial is currently testing the protective effects of
initiator of inflammation (13)—as predicted by Virchow a the interleikin-1β antagonist canakinumab in patients with
century ago. a past acute coronary syndromes (20). Similarly, the CIRS
trial (21) is evaluating the effects of low-dose methotrex-
The blood vessel on fire ate in patients with coronary artery disease. Here again the
C-reactive protein (CRP), currently widely used as a readout translation of knowledge from basic to clinical science led to
of inflammation, was already discovered in 1930 by William crucial discoveries and hopefully soon to novel therapeutic
Tillett and Thomas Francis at Rockefeller University (14). strategies.
 foreword vii

The renin angiotensin system neprelysin inhibitors, or ARNIs, modulation of plasma

levels of natriuretic peptides became an important thera-
In parallel with these discoveries, the regulation of blood
peutic strategy in heart failure (31) and, possibly, will soon
pressure and its impact on the vasculature has been charac-
be the case in hypertension as well.
terized. Here, the seminal experiment has been performed
by Robert Tigerstedt (22) in 1898 when he injected renal
extracts in the intact rabbit and observed a marked increase The sympathetic nervous system
in blood pressure. He called the proposed mediator ‘renin’. The vasculature is not only regulated by circulating hor-
When Eduardo Braun Menendez discovered angiotensin II mones and local factors derived from the endothelium
in 1939 (23) and, a few years earlier, Harry Goldblatt had and vascular smooth muscle cells, but it is also innervated
demonstrated that a clamp to a renal artery would produce by sympathetic and other fibres that, importantly, regulate
hypertension in dogs (24), an important blood pressure vascular tone and structure. Of note, particularly for short-
regulatory system was being characterized. Sir John Vane, term changes in posture and adaptations of the circulation
Nobel Prize Laureate in 1982, showed in the late 1960s that to increased demand (i.e. during exercise), the sympathetic
angiotensin I was activated in the pulmonary circulation nervous system is of utmost importance.
into angiotensin II by the proposed angiotensin convert- While paravertebral ganglia have already been noted in
ing enzyme on the surface of endothelail cells that was later ancient times by Galen and his followers, their function as a
biochemically and structurally characterized (25). Miguel relay station of nerve traffic within the body was only discov-
Ondetti, Bernard Rubin, and David Cushman, working at ered in the 20th century. Notably, the sympathetic nervous
Squibb laboratories, eventually discovered captopril in 1977, system is closely connected with local and circulating regu-
the first ACE-inhibitor in its class (26), and John Laragh and latory systems: for instance angiotensin II and epinephrine
his team in New York confirmed its clinical use as a blood enhance synaptic neurotransmission, while acetylcholine
pressure remedy (27). reduces it. Finally, the primary neurotransmitter noradrena-
Soon it became clear that the renin angiotensin system line itself limits its own release via activation of presynaptic
was not only a circulating endocrine regulator but, as pro- α2-receptor. Importantly, sympathetic fibers innervate the
posed by Victor Dzau (28), a paracrine system within the kidney vasculature and regulate renal blood flow and, via
vessel wall contributing to oxidative stress via NADPH β-receptors, enhance renin secretion in juxtaglomerular
oxidase and to endothelial dysfunction and structural vas- cells. Thus, all these regulatory systems are tightly intercon-
cular changes typical of hypertension and atherosclerosis nected to allow optimal regulation of the cardiovascular
alike. The clinical importance of these experimental find- system under resting conditions and during exercise.
ings was later confirmed in the HOPE trial with ramipril
and thereafter in several following trials with other ACE- Genetics
inhibitors (29). Gregor Mendel (1822–84) was a monk living in the
Austro-Hungarian Empire in the 19th century and until he
The heart as an endocrine organ discovered the fundamental laws of inheritance, genetics
In the 1980s, Alfonso de Bold in Canada performed—as did not exist. Neglected by his contemporaries, his seminal
had Robert Tigerstedt a century earlier—a simple experi- experiments became only known at the beginning of the
ment when he injected homogenized atrial tissue in an 20th century. Later deoxyribonucleic acid, or DNA, was rec-
intact animal and produced natriuresis (30). The dis- ognized as the carrier of genetic information, and its helical
covery of natriuretic peptides as the natural antagonists structure was described by James Watson and Francis Crick
of the renin angiotensin system further advanced our in 1953 (32).
understanding of cardiovascular control. Indeed, these Soon these discoveries were applied to biological research
peptides are released in atrial and myocardial tissue in and, recently, increasingly so in vascular biology. Although
response to physical stimuli and have important effects in most forms of cardiovascular disease are polygenetic in
the vasculature and the kidney as they induce vasodilation, nature with a strong environmental influence, genetics in
inhibit the renin angiotensin system and cause natriure- particular helped in animal research to delineate mecha-
sis. Importantly, these discoveries were translated to the nisms of disease using transgenic and knockout models
clinical level where natriuretic peptides, in particular brain to study hypertension (33), its impact on blood vessels
natriuretic peptides, became useful biomarkers. Finally, (34), as well as to study atherosclerosis (35). As it turned
with the introduction of angiotensin receptor antagonists/ out, with the exception of monogenetic diseases such as
viii 
foreword

cardiomyopathies or channelopathies, the contribution of in health and disease. Notably, research went in both direc-
genetics in atherosclerosis and its clinical sequelae such as tions: from bench to bedside and from the bedside to the
myocardial infarction and stroke is complex and strongly bench (Fig. P.1). Indeed, vascular biologists have stimulated
modulated by environmental factors (36,37). However, clinical scientists to perform studies and trials in patients
Mendelian randomization studies have helped to delineate and results of clinical studies have stimulated research at the
genes involved in cardiovascular conditions (38). A major bench side.
success story is the discovery of mutations in the PCSK9 The publication of the current ESC Textbook of Vascular
gene that led to the characterization of this protein in the Biology (edited by Robert Krams and Magnus Bäck) is timely,
regulation of LDL-receptors and, in turn, atherosclerosis since it comes at a moment at which vascular biology as a
and eventually to the development of PCSK9 inhibitors (39). science has fulfilled its promise. Indeed, it has shown that it
Also, we have learnt that gene expression is highly regu- can provide insights into the molecular mechanisms of vas-
lated by transcription factors binding to the promoter region cular disease and that such findings can be translated to the
of distinct genes. These in turn are activated by specific signal clinical level to the benefit of cardiovascular patients. The
transduction pathways linked to surface receptors. Recently, editors and the authors should be congratulated for such an
non-coding RNAs have been discovered that profoundly excellent textbook which, I am sure, will stimulate the next
modulate gene expression (40). A vast number of microRNAs generation of vascular biologists and established investiga-
with an array of effects under physiological conditions and in tors alike. And indeed, this is truly needed as many secrets
disease states have been described and indeed specific signa- of vascular biology wait to be discovered.
tures of them might become useful biomarkers at the clinical
Thomas F. Lüscher, MD, FESC, FRCP
level (41) and possibly even as therapeutic tools or targets.
Professor and Chairman of Cardiology,
University Hospital Zurich;
Vascular biology—a success story Director of the Center for Molecular Cardiology,
Thus, over recent decades vascular biology has contributed University Zurich, Switzerland
immensely to the understanding of cardiovascular function Zurich, 16 January 2017

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1987;59(2):A59–A65. 41. Jakob P, Kacprowski T, Briand-Schumacher S, et al. Profiling and
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╇ Editors and section editors (left to right): Robert Krams, Giuseppina Caligiuri, Imo Hoefer, Marie-Luce Bochaton-Piallat, and Magnus Bäck (missing from
photo: Paul Evans and Esther Lutgens).
 Preface

A few years ago, the Working Group on Atherosclerosis and to homogenize the book. Through all these QC steps we
Vascular Biology decided that a good European project think we have created an excellent textbook.
would be the coordination of a new European Society of We were able to get the support of the top European
Cardiology supported vascular biology textbook. This idea vascular biologists. As a consequence, this book offers a
coincided with the high expectation of a unified Europe and compendium of topics written by the best scientists in
the knowledge that an ESC-supported vascular textbook was Europe on topics very relevant for the field. Due to their
missing. Furthermore, the vascular biology and atheroscler- skills, the chapters are not only a source for young scientists
osis research community in Europe is active and thriving, and students, but also offer interesting reading for experts
and can be considered world-leading. As a consequence, all in the field. Some of the invited authors laudably chose to
ingredients for an excellent European vascular biology text introduce young scientists as co-authors but guaranteed
book were present and the working group decided to initi- their support and their hard work, and their knowledge is
ate this large, but important project. This preface describes why this book has reached such a high quality.
in larger detail the philosophy behind this book. The dissemination of the authors’ vast knowledge and
In 2012, when the ESC turned their interest towards expertise in a single volume will make The ESC Textbook
basic science, the working group Vascular Biology and of Vascular Biology a useful companion for undergradu-
Atherosclerosis of the European Society of Cardiology ates in medicine and biology, but also for young scientists
started discussions on publishing joint papers as road maps and early career staff. It has also been our aim to provide a
for trainees and young scientists. During those discussions comprehensive reference work for cardiologists and other
the idea of writing a textbook was suggested by the editors clinical specialties dealing with vascular diseases and vas-
and the entire working group realized the power of the idea: cular imaging. Indeed, we emphasize the importance of
a first ESC-supported vascular biology text book was coher- vascular biology for the understanding of both physiological
ent to the ideals of a unified Europe and within the realm and pathophysiological processes in the vascular wall, and
of the ESC. It was initially discussed in detail whether it for accomplishing future endeavours in medical research.
was a textbook for undergraduates in the universities or for It has been a pleasure for us working with such an excel-
postgraduates, pre-clinic and clinic. We decided to supply lent team of section editors, whose hard work should be
the information for all interested, including undergraduates especially acknowledged. We are also grateful for the sup-
and postgraduates, as this would appeal more to the poten- port we received for this book project from the European
tial authors. To organize the textbook we decided for two Society of Cardiology and, in particular, the Working Group
major editors, and multiple section editors. The carefully on Atherosclerosis and Vascular Biology. Finally, this book
selected section editors are experts of the section they coor- would not have been possible without the commitment and
dinate and as such evaluated the quality of each individual hard work of the contributing authors, who we thank from
chapter in their section. Their work has, therefore, been of the bottom of our hearts.
tremendous value to the quality of this book. The two editors
subsequently read all chapters to provide a second step of Magnus Bäck
QC, and finally the publisher supplied professional support Robert Krams
 Contents

Section editors and contributors╇ xv 8 Arteriogenesis versus angiogenesis╇ 105

Peter Carmeliet, Guy Eelen, and Joanna Kalucka
Abbreviations╇ xix
9 The lymphatic system╇ 123
Sinem Karaman, Aleksanteri Aspelund, Michael Detmar,
SECTION I and Kari Alitalo
Foundation of the vascular wall
Section introduction: Paul Evans╇ 3 SECTION III
1 Structure and cell biology of the Pathogenesis of atherosclerosis
vessel wall ╇ 5 Section introduction: Imo Hoefer╇ 141
Bibi S. van Thiel, Ingrid van der Pluijm, Roland Kanaar,
A.H. Jan Danser, and Jeroen Essers 10 Atherosclerosis—a short history╇ 143
Claudia Monaco and Esther Lutgens
2 Physiology of blood vessels╇ 17
Victor W.M. van Hinsbergh 11 Pathogenesis of atherosclerosis: lipid
metabolism╇ 149
3 Physical processes in the vessel╇ 31
Olov Wiklund and Jan Borén
T. Christian Gasser
12 Biomechanical theories of atherosclerosis╇ 163
4 Immunology of the vessel wall╇ 43
Jolanda J. Wentzel, Ethan M. Rowland, Peter D. Weinberg,
Göran K. Hansson and Robert Krams
5 Animal models to study pathophysiology of the 13 Atherosclerosis: cellular mechanisms╇ 181
vasculature╇ 53 Esther Lutgens, Marie-Luce Bochaton-Piallat, and
Wenduo Gu, Yao Xie, and Qingbo Xu Christian Weber

SECTION II 14 Molecular mechanisms╇ 199

Claudia Monaco and Giuseppina Caligiuri
Biology of the vasculature╇
Section introduction: Marie-Luce SECTION IV
Bochaton-Piallat╇ 71
Pathophysiology of other cardiovascular
6 The endothelial cell╇ 73 diseases
Ingrid Fleming, Brenda R. Kwak, and Merlijn J. Meens
Section introduction: Esther Lutgens╇ 217
7 Vascular smooth muscle cells╇ 91
Marie-Luce Bochaton-Piallat, Carlie J.M. de Vries, and 15 Valvular heart disease╇ 219
Guillaume J. van Eys Petri T. Kovanen and Magnus Bäck
xiv contents

16 Biology of vascular wall dilation 18 Pathophysiology of thrombosis╇ 277

and rupture╇ 241 Lina Badimon, Felix C. Tanner, Giovanni G. Camici, and
Jean-Baptiste Michel Gemma Vilahur
17 Pathophysiology of vasculitis╇ 253 19 Vascular pathophysiology of hypertension╇ 291
Enrico Tombetti and Justin C. Mason Tomasz J. Guzik and Rhian M. Touyz
20 Adventitia and perivascular adipose tissue—the
SECTION V integral unit in vascular disease╇ 309
Vascular-associated pathologies Zhihong Yang and Xiu-Fen Ming
Section introduction: Giuseppina Caligiuri╇ 275 Index╇ 321
 Section editors and
contributors

Section editors Aleksanteri Aspelund

Wihuri Research Institute and Translational Cancer Biology
Magnus Bäck Program, Biomedicum Helsinki, University of Helsinki,
Department of Cardiology, Karolinska University Hospital, Helsinki, Finland
Stockholm, Sweden
Lina Badimon
Marie-Luce Bochaton-Piallat Cardiovascular Research Center (CSIC-ICCC), Hospital de la
Department of Pathology and Immunology, Faculty of Medicine, Santa Creu i Sant Pau (HSCSP), Barcelona, Spain
University of Geneva, Geneva, Switzerland
Jan Borén
Giuseppina Caligiuri Department for Experimental and Clinical Medicine,
French National Institute of Medical Research (INSERM) and Sahlgrenska Academy at University of Gothenburg, Gothenburg,
Cardiology, University Hospital X. Bichat, Paris, France Sweden
Paul Evans Giovanni G. Camici
Department of Cardiovascular Science, University of Sheffield, UK; Cardiology, Center for Molecular Cardiology, University of
and ESC Working Group on Atherosclerosis and Vascular Biology
Zürich, Zürich, Switzerland
Imo Hoefer
Peter Carmeliet
Department of Clinical Chemistry and Hematology,
Vesalius Research Center, VIB, University of Leuven, Leuven,
University Medical Center Utrecht, The Netherlands
Belgium
Robert Krams
A.H. Jan Danser
Faculty of Engineering, Department of Bioengineering, Imperial
Division of Vascular Medicine and Pharmacology, Department
College, London, UK
of Internal Medicine, Erasmus Medical Center, Rotterdam, The
Esther Lutgens Netherlands
Department of Medical Biochemistry, Academic Medical Center,
Michael Detmar
University of Amsterdam, The Netherlands; and Institute for
Institute of Pharmaceutical Sciences, Swiss Federal Institute of
Cardiovascular Prevention, Ludwig Maximilian’s University,
Technology, Zurich, Switzerland
Munich, Germany
Guy Eelen
Vesalius Research Center, VIB, University of Leuven, Leuven
Contributors Belgium
Kari Alitalo Jeroen Essers
Wihuri Research Institute and Translational Cancer Biology Department of Molecular Genetics, Department of Vascular
Program, Biomedicum Helsinki, University of Helsinki, Surgery and Department of Radiation Oncology, Erasmus
Helsinki, Finland Medical Center, Rotterdam, The Netherlands
xvi section editors and contributors

Ingrid Fleming Xiu-Fen Ming

Institute for Vascular Signalling, Centre for Molecular Medicine, Cardiovascular and Aging Research, Department of Medicine,
Goethe University, Frankfurt am Main, Germany Division of Physiology, Faculty of Science, University of
Fribourg, Fribourg, Switzerland
T. Christian Gasser
KTH Solid Mechanics, School of Engineering Sciences, KTH Claudia Monaco
Royal Institute of Technology, Stockholm, Sweden The Kennedy Institute of Rheumatology, University of Oxford,
Oxford, UK
Wenduo Gu
Cardiovascular Division, King’s College London BHF Centre, Ethan M. Rowland
London, UK Faculty of Engineering, Department of Bioengineering, Imperial
College, London, UK
Tomasz J. Guzik
Institute of Cardiovascular and Medical Sciences, BHF Glasgow Felix C. Tanner
Cardiovascular Research Centre for Excellence, University Institute of Physiology, University of Zürich, Zürich,
of Glasgow, UK and Department of Medicine, Jagiellonian Switzerland
University School of Medicine, Krakow, Poland
Enrico Tombetti
Göran K. Hansson Allergy and Clinical Immunology, San Raffaele Scientific
Center for Molecular Medicine and Department of Medicine, Institute, Milan, Italy
Karolinska University Hospital, Karolinska Institutet,
Rhian M. Touyz
Stockholm, Sweden
Institute of Cardiovascular and Medical Sciences, BHF Glasgow
Roland Kanaar Cardiovascular Research Centre for Excellence, University of
Department of Molecular Genetics and Department of Glasgow, UK
Radiation Oncology, Erasmus Medical Center, Rotterdam,
Guillaume J. van Eys
The Netherlands
Department of Genetics and Cell Biology, Cardiovascular
Joanna Kalucka Research Institute, Maastricht, The Netherlands
Vesalius Research Center, VIB, University of Leuven, Leuven,
Victor W.M. van Hinsbergh
Belgium
Department of Physiology, Institute for Cardiovascular Research,
Sinem Karaman VU University Medical Center, Amsterdam, The Netherlands
Institute of Pharmaceutical Sciences, Swiss Federal Institute of
Ingrid van der Pluijm
Technology, ETH Zurich, Zurich, Switzerland
Department of Molecular Genetics and Department of Vascular
Petri T. Kovanen Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
Wihuri Research Institute, Biomedicum Helsinki, Helsinki,
Bibi S. van Thiel
Finland
Department of Molecular Genetics, Department of Vascular
Brenda R. Kwak Surgery and Division of Vascular Medicine and Pharmacology,
Department of Pathology and Immunology, and Department of Department of Internal Medicine, Erasmus Medical Center,
Medical Specialties—Cardiology, Faculty of Medicine, University Rotterdam, The Netherlands
of Geneva, Geneva, Switzerland
Gemma Vilahur
Justin C. Mason Cardiovascular Research Center (CSIC-ICCC) Hospital de la
Vascular Sciences, Imperial Centre for Translational Santa Creu i Sant Pau (HSCSP), Barcelona, Spain
& Experimental Medicine, Imperial College London,
Carlie J.M. de Vries
Hammersmith Hospital, London, UK
Department of Medical Biochemistry, Academic Medical Center,
Merlijn J. Meens University of Amsterdam, Amsterdam, The Netherlands
Department of Pathology and Immunology, and Department of
Christian Weber
Medical Specialties—Cardiology, Faculty of Medicine, University
Institute for Cardiovascular Prevention, Ludwig Maximilian's
of Geneva, Geneva, Switzerland
University, Munich, Germany
Jean-Baptiste Michel
Peter D. Weinberg
Inserm Research Director, Denis Diderot University, Xavier
Faculty of Engineering, Department of Bioengineering, Imperial
Bichat Hospital, Paris, France
College, London, UK
 section editors and contributors xvii

Jolanda J. Wentzel Yao Xie

Biomechanics Laboratory, Biomedical Engineering, Cardiology Cardiovascular Division, King’s College London BHF Centre,
Department, Erasmus MC, The Netherlands London, UK
Olov Wiklund Qingbo Xu
Department for Experimental and Clinical Medicine, Sahlgrenska Cardiovascular Division, King’s College London BHF Centre,
Academy at University of Gothenburg, Gothenburg, Sweden London, UK
Zhihong Yang
Cardiovascular and Aging Research, Department of Medicine,
Division of Physiology, Faculty of Science, University of
Fribourg, Fribourg, Switzerland
 Abbreviations

AAV antibody-associated vasculitis NAFLD non-alcoholic fatty liver disease

ACE angiotensin-converting enzyme NFkB nuclear factor kappa B
AMPK 5’AMP-activated protein kinase NOD nuclear oligomerization domain
ANP atrial natriuretic peptide PAMP pathogen-associated molecular patterns
BBB blood–brain barrier PCI percutaneous coronary intervention
BMP4 bone morphogenetic protein 4 PDGF platelet-derived growth factors
C compliance PET positron emission tomography
ChIP chromatin immunoprecipitation PIV particle image velocimetry
COUP-TFII Chicken ovalbumin upstream promoter- PRRs pattern recognition receptors
transcription factor II pVAT perivascular adipose tissue
COXs cyclo-oxygenases PVAT perivascular adipose tissue
ECM extracellular matrix RAAS renin–angiotensin–aldosterone system
EDHFs endothelium-derived hyperpolarization factors ROS reactive oxygen species
EETs epoxyeicosatrienoic acids SDF sidestream-dark field flowmetry
eNOS endothelial NO synthase shh sonic hedgehog
FGF-2 fibroblast growth factor 2 SMA smooth muscle actin
FH familial hypercholesterolaemia SMC smooth muscle cells
FSI fluid structure interaction SM-MHCs smooth muscle myosin heavy chains
GAGs glycosaminoglycans SVR systemic vascular resistance
ICAM-1 intercellular cell-adhesion molecule 1 TCFA thin-cap fibroatheroma
IDO indoleamine dioxygenase TFPI tissue factor pathway
IL interleukins TGF-β transforming growth factor β
ILT intraluminal thrombus TLRs Toll-like receptors
LAM leukocyte adhesion molecules TNF-α tumour necrosis factor-α
LDL low-density lipoprotein UTS ultimate tensile strength
MAP mean arterial pressure VCAM-1 vascular cell-adhesion molecule 1
MAPK mitogen-activated protein kinase VEGF-A vascular endothelial growth factor
M-CSF macrophage-colony stimulating factor VEGFR vascular endothelial growth factor receptor
MLC myosin light chain VLDL very low-density lipoprotein
MLU medial laminar units VSMC vascular smooth muscle cell
MMPs matrix metalloproteinases WSS wall shear stress
MRI magnetic resonance imaging
 SECTION I

Foundation of the
vascular wall

1 Structure and cell biology of the vessel wall╇ 5

Bibi S. van Thiel, Ingrid van der Pluijm, Roland Kanaar, A.H. Jan Danser, and Jeroen Essers
2 Physiology of blood vessels╇ 17
Victor W.M. van Hinsbergh
3 Physical processes in the vessel╇ 31
T. Christian Gasser
4 Immunology of the vessel wall╇ 43
Göran K. Hansson
5 Animal models to study pathophysiology of the vasculature╇ 53
Wenduo Gu, Yao Xie, and Qingbo Xu
Section introduction
Paul Evans
The survival and function of cells relies on a continuous supply of nutrients,
metabolites, and gases, and the expulsion of toxic materials. The transfer of mole-
cules from the environment to the cell is a challenge in metazoans where diffusion
provides insufficient molecular transport in multicellular tissues. Because of this,
the emergence of multicellular animals was closely paralleled with the evolution
of sophisticated vascular systems. The purpose of this section is to introduce the
reader to the fundamental properties and functions of the mammalian vascular
system, thereby laying foundations that can be developed in later chapters.
In Chapter 1, the architecture of blood vessels (including arteries, veins, and
capillaries) is described and the properties of their constituent parts (vascular,
endothelial, and smooth muscle cells) are also outlined. This description of vas-
cular form leads on to Chapter 2, which describes the physiological properties of
blood vessels. This chapter includes the mechanisms that regulate blood pressure
and flow, and the fundamental principles that underlie the exchange of materials
between the vasculature and the tissues that it serves. In addition to regulation
through physiological systems, blood vessels are also strongly influenced by their
physical environment. This topic is introduced in Chapter 3, which summarizes
the factors that control mechanical loading of the vessel wall and its effects on vas-
cular biology. This chapter also includes a description of the interaction of flowing
blood with the vessel wall and the effects of this on endothelial cell behaviour.
One of the endothelial functions that is particularly sensitive to fluid mechanics is
the ability to recruit immune cells, a subject that is discussed in Chapter 4. Here,
the routes that immune cells follow as they migrate into the vascular wall and the
mechanisms that control these processes are described. Moreover, the role of
immune cells and inflammation in the initiation and progression of atheroscler�
osis (a disease of arteries) is discussed. The final chapter in this foundation section
focuses on the use of animal models in vascular biology research. It provides an
appraisal of several mouse, rat, rabbit, and pig models of atherosclerosis and other
vascular diseases, including a description of the strengths and caveats of each
model.
Together, this collection of chapters will equip the reader for the subsequent
sections of this textbook by providing an extensive overview of the physical prop-
erties, anatomy, cell biology, physiology, and immunology of the vessel wall.
 CHAPTER 1

Structure and cell biology

of the vessel wall
Bibi S. van Thiel, Ingrid van der Pluijm, Roland
Kanaar, A.H. Jan Danser, and Jeroen Essers

Content
Introduction╇5
Introduction
Structure of the vascular wall╇6 A healthy heart pumps about 6,000–8,000 litres of blood around the body each day.
Components of the vascular wall╇8 Blood is carried through the body via blood vessels. The blood vessels form a closed
Types of blood vessels╇11
Ageing and the vascular wall╇14 system that begins and ends at the heart. In mammals, blood circulates through
Summary╇16 two separate circuits: the pulmonary circuit and the systemic circuit (% Fig. 1.1).
◆ Pulmonary circuit: the right ventricle of the heart pumps blood into the lungs,
where waste gases are exchanged for oxygen, after which the blood is trans-
ported back to the left atrium of the heart.
◆ Systemic circuit: the left ventricle pumps oxygenated blood to all tissues and
organs of the body via the aorta, after which deoxygenated blood is transported
back to the right atrium of the heart.
% Figure 1.1 gives a simplified overview of the blood flow through the body,
where deoxygenated blood is depicted in blue and oxygenated blood is depicted
in red. Note that somewhat counter-intuitively, deoxygenated blood does not
refer to blood without oxygen. Rather, it refers to a lower oxygenation grade than
that of oxygenated blood because a certain amount of oxygen has been delivered
to tissues. As a result, deoxygenated blood still contains about 75% of oxygen
compared to oxygenated blood.
A well-functioning cardiovascular system is essential for all vertebrates. The
blood vessels are a conduit for a variety of molecules, such as nutrients, oxygen,
and waste products, to and from all parts of the body. Blood vessels have several
main functions:
1. Distribution of blood containing nutrients (e.g. glucose and amino acids),
oxygen (O2), water, and hormones to all the tissues and organs of the body.
2. Removal of metabolic waste products and carbon dioxide (CO2) from the
tissues to the excretory organs and the lungs, respectively.
3. Regulation of blood pressure.
4. Maintenance of constant body temperature (thermoregulation).
6 Chapter 1╇ structure and cell biology of the vessel wall

released to the surroundings. In contrast, blood vessels near

Lungs
Capillary bed
the skin’s surface can constrict, reducing heat loss through
of lungs the skin when needed under cold circumstances.

Structure of the vessel wall

Pulmonary circuit
Blood vessels need to be well-constructed, as they have to
withstand the pressure of circulating blood through the body
every day. The vessel wall is arranged in three distinct lay-
ers, termed tunica: an inner layer (tunica intima), a middle
layer (tunica media), and an outer layer (tunica adventitia)
(% Fig. 1.2). These layers mainly contain endothelial cells,
To the heart From the heart vascular smooth muscle cells, and extracellular matrix,
Heart
including collagen and elastic fibres.

Systemic circuit Tunica intima

The tunica intima (‘inner coat’) is the innermost layer of a
blood vessel. In healthy vessels, it consists of a thin single
layer of endothelial cells, which are in direct contact with
the blood in the lumen, as well as a subendothelial layer
Capillary bed made up mostly by connective tissue. The single layer of
of tissue endothelial cells, called endothelium, has a smooth surface
Fig. 1.1╇ Schematic overview of the cardiovascular circulatory system. that minimizes the friction of the blood as it moves through
Note that arteries and oxygenated blood are depicted in red and veins and the lumen. The endothelium plays a role in vascular perme-
deoxygenated blood are depicted in blue.
ability, inflammation, coagulation, and vascular tone, which
refers to the maximal degree of contraction by vascular
Distribution of nutrients, gases, and smooth muscle cell relative to its maximally dilated state. The
removal of waste products subendothelial layer, also called the basal lamina, provides a
physical support base for the endothelial cells and flexibility
The primary function of blood vessels is to transport blood of the vessel for stretching and recoil. Moreover, it guides cell
around the body, thereby supplying organs with the neces- and molecular movement during tissue repair of the vessel
sary O2 and nutrients. At the same time, the vessels remove wall. The tunica intima is the thinnest layer of the blood ves-
waste products and CO2 to be processed or removed from sel and minimally contributes to the thickness of the vessel
the body. wall. In arteries and arterioles, the outer margin of the tunica
intima is separated from the surrounding tunica media by
Regulation of blood pressure the internal elastic membrane, a thick layer of elastic fibres.
Blood vessels control blood pressure by changing the The internal elastic membrane provides structure and elas-
diameter of the vessel through either constriction (vaso- ticity to the vessel and allows diffusion of materials through
constriction) or dilation (vasodilation). Variations in blood the tunica intima to the tunica media. Microscopically,
pressure occur in various parts of the circulation depending the lumen and the tunica intima of an artery appear wavy
on the diameter of the vessel (see % Chapter 3). because of the partial constriction of the vascular smooth
muscle cells in the tunica media, the middle layer of the blood
Maintenance of constant body temperature vessel, whereas the tunica intima of a vein appears smooth.
(thermoregulation)
Blood vessels help maintain a stable body temperature by Tunica media
controlling the blood flow to the surface area of the skin. To The middle layer, tunica media, is considered to be the
prevent overheating, blood vessels near the surface of the muscular layer of the blood vessel as it primarily contains
skin can dilate, allowing excessive heat of the blood to be circularly arranged smooth muscle fibres together with
 structure of the vessel wall 7

Tunica adventitia Tunica media Tunica intima

Endothelium

Connective tissue
Tunica intima Internal elastic membrane

Muscle fibres

Tunica media

Elastic fibre

External elastic membrane

Tunica adventitia
Connective tissue

Fig. 1.2╇ General structure of the vessel wall, showing the tunica intima, tunica media, and tunica adventitia, and a close-up depicting the different structures
within these layers.

extracellular matrix, mostly elastin sheets. It is often the (nervi vasorum). The tunica media is separated from the
thickest layer of the arterial wall and much thicker in arteries tunica adventitia by a dense elastic lamina called the exter-
than in veins. The tunica media provides structural sup- nal elastic membrane. Under the microscope, these laminae
port as well as vasoreactivity (the ability of blood vessels to appear as wavy lines. This structure is usually not apparent
contract or to relax in response to stimuli) and elasticity to in small arteries and veins.
the blood vessel. The primary role of the vascular smooth
muscle cells is to regulate the diameter of the vessel lumen.
Concerning blood pressure regulation, the vascular smooth Tunica adventitia
muscle cells in the tunica media can either contract caus- The tunica adventitia (also known as tunica externa) is the
ing vasoconstriction or relax causing vasodilation. During outermost layer of the vessel wall, surrounding the tunica
vasoconstriction, the lumen of the vessel narrows, leading to media. The adventitia is predominantly made up by extra-
an increase in blood pressure, whereas vasodilation widens cellular matrix (collagen and elastic fibres), nutrient vessels
the lumen allowing blood pressure to drop. Both vasocon- (vasa vasorum), and autonomic nerves (nervi vasorum).
striction and vasodilation are partially regulated by nerves Fibroblasts and numerous macrophages are also present in
8 Chapter 1╇ structure and cell biology of the vessel wall

this layer. The tunica adventitia is often the thickest layer are in direct contact with blood. They form a single-cell
in veins, sometimes even thicker than the tunica media in layer (monolayer) called the endothelium, which has been
larger arteries. The tunica adventitia helps to anchor the ves- estimated to cover a surface area of more than 1,000 m2 in
sel to the surrounding tissue and provides strength to the humans. The morphological shape of endothelial cells varies
vessels as it protects them from overexpansion. across the circulatory system (1). In large arteries, endothe-
lial cells are aligned and elongated in the direction of the
Vasa vasorum blood flow, whereas in regions of disturbed flow, e.g. near
Characteristic of the adventitial layer is the presence of small bifurcations, endothelial cells are more round and do not
blood vessels, called the vasa vasorum. The vasa vasorum align in a specific direction. Varying among the vascular
supplies blood and nourishment to the tunica adventitia tree, endothelial cells are between 0.2 and 2.0 µm thick and
and outer parts of the tunica media, as these layers are too 1 to 20 µm long. They are joined together by tight junctions,
thick to be nourished merely by diffusion from blood in the which restrict the transportation of large molecules across
lumen, and removes ‘waste’ products. Because of the thick the endothelium. Endothelial cells are active contributors to
and muscular walls of the arteries, the vasa vasorum are a variety of vessel-related activities, including permeability,
more frequent in the wall of arteries than in the wall of veins. vascular tone, and haemostasis.
Vascular endothelial cells have several important func-
tions (% Box 1.1).
The endothelium has a strategic position in the vessel wall,
Components of the vascular wall right between the circulating blood and the vascular smooth
muscle cell. From this position, the endothelium plays a vital
The vascular wall is composed of many cell types and con-
role in controlling vascular function, as it is able to respond
stituents that influence the diameter and functional control
to mechanical and hormonal signals and receive informa-
of the vessel wall. Several main cell types include endothe-
tion from cellular constituents of the vessel wall. Endothelial
lial cells, vascular smooth muscle cells, and immune cells
cells are highly dynamic as they need to interpret changes
(% Fig. 1.3). Interaction between these cell types allows the
in blood composition and mechanical changes, and respond
vessel to adapt to alterations in pressure and various physical
properly to several stimuli, either physical or chemical, by
stimuli by either dilation or contraction.
producing a variety of factors that contribute to the control
of vascular tone, vascular inflammation, cellular adhesion,
Endothelium haemostasis, and coagulation. For instance, the endothelium
Vascular endothelial cells lining the entire circulatory sys- serves as a semi-permeable barrier, restricting and control-
tem, from the heart and arteries to the small capillary beds, ling the movement of fluids, molecules, and cells across the

Endothelium

Smooth muscle cell Connective tissue

Elastic lamina

Neutrophil

Macrophage

Fig. 1.3╇ Summary of the major components

of the vessel wall. Nerve Blood vessel (vasa vasorum)
Exploring the Variety of Random
Documents with Different Content
 At last they came to their journey’s end, and stopped at the gate
of a fine house: “Now, Billy,” said the little man, “do as you see me
do, and follow me close; but as you did not know your horse’s head
from his tail, mind that your own head does not spin round until you
can’t tell whether you are standing on it or on your heels: for
remember that old liquor, though able to make a cat speak, can
make a man dumb.”
The little man then said some queer kind of words, out of which
Billy could make no meaning; but he contrived to say them after him
for all that; and in they both went through the key-hole of the door,
and through one key-hole after another, until they got into the wine
cellar, which was well-stored with all kinds of wine.
The little man fell to drinking as hard as he could, and Billy, no
way disliking the example, did the same. “The best of masters are
you, surely,” said Billy to him; “no matter who is the next; and well
pleased will I be with your service if you continue to give me plenty
to drink.”
“I have made no bargain with you,” said the little man, “and will
make none; but up and follow me.”
Away they went through key-hole after key-hole; and each
mounting upon the rush which he left at the hall door, scampered
off, kicking the clouds before them like snowballs, as soon as the
words, “Borram, Borram, Borram,” had passed their lips.
 When they came back to the Fort-field, the little man dismissed
Billy, bidding him be there the next night at the same hour. Thus did
they go on, night after night, shaping their course one night here,
and another night there—sometimes north, and sometimes east, and
sometimes south, until there was not a gentleman’s wine-cellar in all
Ireland they had not visited and could tell the flavour of every wine
in it as well—ay, better than the butler himself.
One night when Billy MacDaniel met the little man as usual in the
Fort-field, and was going to the bog to fetch the horses for their
journey, his master said to him, “Billy, I shall want another horse to-
night, for maybe we may bring back more company than we take.”
So Billy, who now knew better than to question any order given to
him by his master, brought a third rush much wondering who it
might be that would travel back in their company, and whether he
was about to have a fellow-servant. “If I have,” thought Billy, “he
shall go and fetch the horses from the bog every night; for I don’t
see why I am not, every inch of me, as good a gentleman as my
master.”
Well, away they went, Billy leading the third horse, and never
stopped until they came to a snug farmer’s house in the county
Limerick, close under the old castle of Carrigogunniel, that was built
they say, by the great Brian Boru. Within the house there was great
carousing going forward, and the little man stopped outside for
some time to listen; then turning round all of a sudden said, “Billy, I
will be a thousand years old to-morrow.”
“God bless us, sir,” said Billy, “will you?”
“Don’t say these words again, Billy,” said the little man, “or you
will be my ruin for ever. Now, Billy, as I will be a thousand years in
the world to-morrow, I think it is full time for me to get married.”
“I think so too, without any kind of doubt at all,” said Billy, “if ever
you mean to marry.”
“And to that purpose,” said the little man, “have I come all the
way to Carrigogunniel; for in this house, this very night, is young
Darby Riley going to be married to Bridget Rooney; and as she is a
tall and comely girl and has come of decent people, I think of
marrying her myself and taking her off with me.”
 “And what will Darby Riley say to that?” said Billy.
“Silence,” said the little man, putting on a mighty severe look: “I
did not bring you here with me to ask questions;” and without
holding further argument, he began saying the queer words which
had the power of passing him through the key-hole as free as air,
and which Billy thought himself mighty clever to be able to say after
him.
In they both went; and for the better viewing the company, the
little man perched himself up as nimbly as a cock sparrow upon one
of the big beams which went across the house over all their heads,
and Billy did the same upon another facing him; but not being much
accustomed to roosting in such a place, his legs hung down as
untidy as may be, and it was quite clear he had not taken pattern
after the way in which the little man had bundled himself up
together. If the little man had been a tailor all his life he could not
have sat more contentedly upon his haunches.
There they were, both master and man, looking down upon the
fun that was going forward; and under them were the priest and
piper, and the father of Darby Riley, with Darby’s two brothers and
his uncle’s son; and they were both the father and the mother of
Bridget Rooney, and proud enough the old couple were that night of
their daughter, as good right they had; and her four sisters, with
bran new ribbons in their caps, and her three brothers all looking as
clean and as clever as any three boys in Munster, and there were
uncles and aunts, and gossips and cousins enough besides to make
a full house of it; and plenty was there to eat and drink on the table
for every one of them, if they had been double the number.
Now it happened, just as Mrs Rooney had helped his reverence to
the first cut of the pig’s head which was placed before her,
beautifully bolstered up with white savoys, that the bride gave a
sneeze, which made every one at table start, but no one said, “God
bless us.” All thinking that the priest would have done so, as he
ought if he had done his duty, no one wished to take the word out of
his mouth, which unfortunately was pre-occupied with pig’s head
and greens. And after a moment’s pause the fun and merriment of
the bridal feast went on without the pious benediction.
 Of this circumstance both Billy and his master were no inattentive
spectators from their exalted stations. “Ha,” exclaimed the little man,
throwing one leg from under him with a joyous flourish, and his eye
twinkled with a strange light, whilst his eyebrows became elevated
into the curvature of Gothic arches—“Ha,” said he, leering down at
the bride, and then up at Billy, “I have half of her now, surely. Let
her sneeze out twice more, and she is mine, in spite of priest, mass-
book, and Darby Riley.”
Again the fair Bridget sneezed; but it was
so gently, and she blushed so much, that few
except the little man took, or seemed to take,
any notice; and no one thought of saying
“God bless us.”
Billy all this time regarded the poor girl with
a most rueful expression of countenance; for
he could not help thinking what a terrible
thing it was for a nice young girl of nineteen,
with large blue eyes, transparent skin, and
dimpled cheeks, suffused with health and joy,
to be obliged to marry an ugly little bit of a
man, who was a thousand years old barring a
day.
At this critical moment the bride gave a third sneeze, and Billy
roared out with all his might, “God save us.” Whether this
exclamation resulted from his soliloquy, or from the mere force of
habit, he never could tell exactly himself; but no sooner was it
uttered than the little man, his face glowing with rage and
disappointment, sprung from the beam on which he had perched
himself, and shrieking out in the voice of a cracked bagpipe, “I
discharge you from my service, Billy MacDaniel—take that for your
wages,” gave poor Billy a most furious kick in the back, which sent
his unfortunate servant sprawling upon his face and hands right in
the middle of the supper table.
If Billy was astonished, how much more so was every one of the
company into which he was thrown with so little ceremony. But
when they heard his story, Father Cooney laid down his knife and
fork, and married the young couple out of hand with all speed; and
Billy MacDaniel danced the Rinka at their wedding, and plenty did he
drink at it too, which was what he thought more of than dancing.

Bottom was mighty glad when his story was over, for he did not
like the feeling that he could not get up from the stool when he
tried, and he did not like to hear how small a voice he was speaking
in; he would have liked to speak big and show what a great fellow
he was in that queer company, but there he sat unable to move, and
roaring as gently as any sucking dove to use his own words. As soon
as he had got to the last word of his story he found that he could
get up and off he floundered to his companions.
“Another fairy this time,” said King Oberon, as though he had not
altogether relished Bottom’s story; “the Danish Elves have told us
nothing yet.”
At this, which was of course equal to a command, a Danish Elf
came forward, seated himself and began to tell about
 The Elf Hill
Some lizards were nimbly running in and out of the clefts in an old
tree. They understood each other very well, for they all spoke lizard
language.
“What a rumbling and grumbling is going on inside the old Elf-hill,”
said one of the lizards. “I have not closed my eyes for the last two
nights for the noise. I might just as well be having toothache, for all
the sleep I get!”
“There is something up inside,” said the other lizard. “They
propped up the top of the hill on four red posts till cockcrow this
morning, to air it out thoroughly; and the elf maidens have been
learning some new dancing steps, which they are always practising.
There certainly must be something going on.”
“Yes, I was talking to an earthworm of my acquaintance about it,”
said the third lizard. “He came straight up out of the hill, where he
had been boring into the earth for days and nights. He had heard a
good deal, for the miserable creature can’t see, but it can feel its
way, and plays the part of eavesdropper to perfection. They are
expecting visitors in the Elf-hill, grand visitors; but who they are the
earthworm refused to say or perhaps he did not know. All the will-o’-
the-wisps are ordered for a procession of torches, as it is called; and
the silver and gold plate, of which there is any amount in the hill, is
all being polished up and put out in the moonlight.”
“Whoever can the strangers be?” said all the lizards together.
“What on earth is happening? Hark! what a humming and
buzzing!”
At this moment the Elf-hill opened, and an elderly elf-maiden
tripped out. She was hollow behind, but otherwise quite attractively
dressed. She was the old elf-king’s housekeeper, and a distant
relative. She wore an amber heart upon her forehead. She moved
her legs at a great pace, “trip, trip.” Good heavens! how fast she
tripped over the ground; she went right down to the night-jar in the
swamp.
“You are invited to the Elf-hill for to-night,” she said to him. “But
will you be so kind as to charge yourself with the other invitations.
You must make yourself useful in other ways, as you don’t keep
house yourself. We are going to have some very distinguished
visitors, goblins, who always have something to say, and so the old
elf-king means to show what he can do.”
“Who is to be invited?” asked the night-jar.
“Well, everybody may come to the big ball, even human beings, if
they can only talk in their sleep, or do something else after our
fashion. But the choice is to be strictly limited for the grand feast.
We will only have the most distinguished people. I have had a battle
with the Elf-king about it; because I hold that we mustn’t even
include ghosts. The merman and his daughters must be invited first.
I don’t suppose they care much about coming on dry land, but I
shall see that they each have a wet stone to sit on, or something
better; so I expect they won’t decline this time. All the old demons
of the first-class, with tails, the River-god, and the wood-sprites. And
then I don’t think we can pass over the Grave-pig, the Hell-horse,
and the Church-grim, although they belong to the clergy, who are
not of our people; but that is merely on account of their office, and
they are closely connected with us, and visit us very frequently.”
“Croak,” said the night-jar, and he flew off to issue the invitations.
The elf-maidens had already begun to dance, and they danced a
scarf-dance, with scarves woven of mist and moonshine; these have
a lovely effect to those who care for that kind of thing. The great
hall in the middle of the Elf-hill had been thoroughly polished up for
the occasion. The floor was washed with moonshine, and the walls
were rubbed over with witches’ fat, and this made them shine with
many colours, like a tulip petal. The kitchen was full of frogs on
spits, stuffed snake skins, and salads of toad-stool spawn, mouse
snouts and hemlock. Then there was beer brewed by the marsh
witch, and sparkling saltpetre wine from the vaults. Everything of the
best, and rusty nails and church window panes among the
kickshaws.
The old Elf-king had his golden crown polished with pounded
slate-pencil, ay, and it was a head-boy’s slate-pencil too, and they
are not so easy to get. They hung up fresh curtains in the bedroom,
and fixed them with the slime of snails. Yes, indeed, there was a
humming and a buzzing.
“Now we will fumigate, with horse-hair and pig’s bristles, and then
I can do no more!” said the old elf-servant.
“Dear father!” said the youngest of the daughters, “are you not
going to tell me who these grand strangers are?”
“Well, well,” he said, “I suppose I must tell you now. Two of my
daughters must prepare themselves to be married,—two will
certainly make marriages. The old Trold chieftain from Norway, that
lives on the Dovrefield among his many rock castles and fastnesses
and gold works, which are better than you would expect, is coming
down here with his two sons. They are coming to look for wives. The
old Trold is a regular honest Norwegian veteran, straightforward and
merry. I used to know him in the olden days, when we drank to our
good fellowship. He came here to fetch a wife, but she is dead now.
She was a daughter of the king of the chalk cliffs at Möen. As the
saying is, ‘he took his wife on the chalk,’ that is, bought her on tick. I
am quite anxious to see the old fellow. The sons, they say, are a pair
of overgrown, ill-mannered cubs; but perhaps they are not so bad; I
daresay they will improve as they grow older. See if you can’t lick
them into shape a bit.”
“And when do they come?” asked one of the daughters.
 “That depends upon wind and weather,” said the Elf-king. “They
travel economically, and they will take their chance of a ship. I
wanted them to come round by Sweden, but the old fellow can’t
bring himself to that yet. He doesn’t march with the times, but I
don’t hold with that!”
At this moment two will-o’-the-wisps came hopping along, one
faster than the other, so of course one arrived before the other.
“They are coming, they are coming!” they cried.
“Give me my crown, and let me stand in the moonlight,” said the
Elf-king.
The daughters raised their scarves and curtseyed to the ground.
There stood the Trold chieftain from the Dovrefield; he wore a
crown of hardened icicles and polished fir-cones, and besides this,
he had on a bear-skin coat and snow-shoes. His sons, on the other
hand, had bare necks and wore no braces, because they were strong
men.
“Is that a hill?” asked the youngest of the brothers, pointing to the
Elf-hill. “We should call it a hole in Norway.”
“Lads!” cried the old man, “holes go inwards, hills go upwards?
Haven’t you got eyes in your heads?”
The only thing that astonished them, they said, was that they
understood the language without any trouble.
“Don’t make fools of yourselves,” said the old man; “one might
think you were only half baked.”
Then they went into the Elf-hill, where the company was of the
grandest, although they had been got together in such a hurry; you
might almost say they had been blown together. It was all charming,
and arranged to suit everyone’s taste. The merman and his
daughters sat at table in great tubs of water, and said it was just like
being at home. Everybody had excellent table manners, except the
two young Norwegian Trolds; they put their feet up on the table, but
then they thought anything they did was right.
“Take your feet out of the way of the dishes,” said the old Trold,
and they obeyed him, but not at once. They tickled the ladies they
took in to dinner with fir-cones out of their pockets; then they pulled
off their boots, so as to be quite comfortable, and handed the boots
to the ladies to hold. Their father the old Trold chieftain, was very
different; he told no end of splendid stories about the proud
Norwegian mountains, and the waterfalls dashing down in white
foam with a roar like thunder. He told them about the salmon
leaping up against the rushing water, when the nixies played with
golden harps. Then he went on to tell them about the sparkling
winter nights when the sledge bells rang and the lads flew over the
ice with blazing lights, the ice which was so transparent that you
could see the startled fish darting away under your feet. Yes, indeed,
he could tell stories, you could see and hear the things he described;
the saw mills going, the men and maids singing their songs and
dancing the merry Halling dance. Huzza! All at once the old Trold
gave the elf housekeeper a smacking kiss, such a kiss it was, and
yet they were not a bit related. Then the elf-maidens had to dance,
first plain dancing, and then step dancing, and it was most becoming
to them. Then came a fancy dance.
Preserve us, how nimble they were on their legs, you couldn’t tell
where they began or where they ended, you couldn’t tell which were
arms and which were legs, they were all mixed up together like
shavings in a saw-pit. They twirled round and round so often that it
made the Hell-horse feel quite giddy and unwell and he had to leave
the table.
“Prrrrr!” said the old Trold. “There is some life in those legs, but
what else can they do besides dancing and pointing their toes and
all those whirligigs?”
“We will soon shew you!” said the Elf-king, and he called out his
youngest daughter; she was thin and transparent as moonshine, and
was the most ethereal of all the daughters. She put a little white
stick in her mouth and vanished instantly; this was her
accomplishment.
But the Trold said he did not like that accomplishment in a wife,
nor did he think his boys would appreciate it. The second one could
walk by her own side as if she had a shadow, and no elves have
shadows.
The third was quite different; she had studied in the marsh
witches’ brewery, and understood larding alder stumps with glow-
worms.
“She will be a good housewife,” said the Trold, and then he
saluted her with his eyes instead of drinking her health, for he did
not want to drink too much.
Now came the turn of the fourth; she had a big golden harp to
play, and when she touched the first string everybody lifted up their
left legs (for all the elfin folk are left legged). But when she touched
the second string everybody had to do what she wished.
“She is a dangerous woman!” said the Trold, but both his sons left
the hill, for they were tired of it all.
“And what can the next daughter do?” asked the old Trold.
“I have learnt to like the Norwegians,” she said, “and I shall never
marry unless I can go to Norway!”
But the smallest of the sisters whispered to the Trold, “that is only
because she once heard a song which said that when the world
came to an end, the rocks of Norway would still stand, and that is
why she wants to go there, she is so afraid of being exterminated.”
“Ho, ho!” said the Trold, “so that slipped out. But what can the
seventh do?”
“The sixth comes before the seventh,” said the Elf-king, for he
could reckon, but she would not come forward.
“I can only tell people the truth,” she said. “Nobody cares for me,
and I have enough to do in making my winding sheet.”
 Now came the seventh and last, what could she do? Well she
could tell stories as many as ever she liked.
“Here are my five fingers,” said the old Trold, “tell me a story for
each one.”
The elf-maiden took hold of his wrist, and he chuckled and
laughed, till he nearly choked. When she came to the fourth finger,
which had a gold ring on it, as if it knew there was to be a betrothal,
the Trold said, “Hold fast what you have got, the hand is yours, I will
have you for a wife myself!” The elf-maiden said that the stories
about Guldbrand, the fourth finger, and little Peter Playman, the
fifth, had not yet been told.
“Never mind, keep those till winter. Then you shall tell us about
the fir, and the birch, and the fairy gifts, and the tingling frost. You
shall have every opportunity of telling us stories; nobody up there
does it yet. We will sit in the Stone Hall, where the pine logs blaze,
and drink mead out of the golden horns of the old Norwegian kings.
The river god gave me a couple. When we sit there the mountain
sprite comes to pay us a visit, and he will sing you the songs of the
Sæter girls. The salmon will leap in the waterfalls, and beat against
the stone wall, but it won’t get in. Ah, you may believe me when I
say that we lead a merry life there in good old Norway. But where
are the lads?”
Yes, where were the lads? They were running about the fields,
blowing out the will-o’-the-wisps, who came so willingly for the
torchlight procession.
“Why do you gad about out there?” said the Trold. “I have taken a
mother for you, now you can come and take one of the aunts.”
But the lads said they would rather make a speech, and drink
toasts; they had no wish to marry. Then they made their speeches,
and drank toasts and tipped their glasses up to shew that they had
emptied them. After that they pulled off their coats and went to
sleep on the table, to show that they were quite at home. But the
old Trold danced round and round the room with his young bride,
and exchanged boots with her, which was grander than exchanging
rings.
 “There is the cock crowing!” said the old housekeeper. “Now we
must shut the shutters, so that the sun may not burn us up.”
Then the hill closed up. But the lizards went on running up and
down the clefts of the tree; and they said to each other, “Ah, how
much I liked the old Trold.”

“I liked the boys better,” said the earthworm, “but then it couldn’t
see, poor, miserable creature that it was.”

“That reminds me of another story,” said the French Fay, who had
already told one story, but was evidently ready and willing to tell
another.
“We don’t want to hear two stories that are like each other,” said
King Oberon.
“Please your Majesty it is not like that which the Danish Elf has
just told, only his one reminded me of mine,” answered the Fay.
“What is it about?” enquired the Queen who remembered how
much she had liked the dainty little creature’s first tale.
“It is a story showing how that which is ugly may become
beautiful through love,” readily responded the French Fay.
“Let us hear it,” said Oberon, “if my Titania wishes it.”
Titania having answered that she certainly did wish it, the Fay
sprang lightly to the stool and began telling the pretty little love
story of
 Riquet with the Tuft
Once upon a time there was a Queen who had a son, so ugly and
misshapen, that it was doubted for a long time whether his form was
really human. A fairy, who was present at his birth, affirmed,
nevertheless, that he would be worthy to be loved, as he would have
an excellent wit; she added, moreover, that by virtue of the gift she
had bestowed upon him, he would be able to impart equal
intelligence to the one whom he loved best. All this was some
consolation to the poor Queen, who was much distressed at having
brought so ugly a little monkey into the world. It is true that the
child was no sooner able to speak than he said a thousand pretty
things, and that in all his ways there was a certain air of intelligence,
with which everyone was charmed. I had forgotten to say that he
was born with a little tuft of hair on his head, and so he came to be
called Riquet with the Tuft; for Riquet was the family name.
About seven or eight years later, the Queen of a neighbouring
kingdom had two daughters. The elder was fairer than the day, and
the Queen was so delighted, that it was feared some harm might
come to her from her great joy. The same fairy who had assisted at
the birth of little Riquet, was present upon this occasion, and in
order to moderate the joy of the Queen, she told her that this little
Princess would have no gifts of mind at all, and that she would be as
stupid as she was beautiful. The Queen was greatly mortified on
hearing this, but, shortly after, she was even more annoyed, when
her second little daughter was born and proved to be extremely ugly.
“Do not distress yourself, madam,” said the fairy to her, “your
daughter will find compensation, for she will have so much
intelligence, that her lack of beauty will scarcely be perceived.”
“Heaven send it may be so,” replied the Queen; “but are there no
means whereby a little more understanding might be given to the
elder, who is so lovely?” “I can do nothing for her in the way of
intelligence, madam,” said the fairy, “but everything in the way of
beauty; as, however, there is nothing in my power I would not do to
give you comfort, I will bestow on her the power of conferring
beauty on any man or woman who shall please her.” As these two
Princesses grew up, their endowments also became more perfect,
and nothing was talked of anywhere but the beauty of the elder, and
the intelligence of the younger. It is true that their defects also
greatly increased with their years. The younger became uglier every
moment, and the elder more stupid every day. She either made no
answer when she was spoken to, or else said something foolish.
With this she was so clumsy, that she could not even place four
pieces of china on a mantelshelf, without breaking one of them, or
drink a glass of water, without spilling half of it on her dress.
Notwithstanding the attraction of beauty, the younger, in whatever
society they might be, nearly always bore away the palm from her
sister. At first everyone went up to the more beautiful, to gaze at
and admire her; but they soon left her for the cleverer one, to listen
to her many pleasant and amusing sayings; and people were
astonished to find that in less than a quarter of an hour, the elder
had not a soul near her, while all the company had gathered round
the younger. The elder, though very stupid, noticed this, and would
have given, without regret, all her beauty, for half the sense of her
sister. Discreet as she was, the Queen could not help often
reproaching her with her stupidity, which made the poor Princess
ready to die of grief.
 One day, when she had gone by herself into a wood, to weep over
her misfortune, she saw approaching her, a little man of very ugly
and unpleasant appearance, but magnificently dressed. It was the
young Prince Riquet with the Tuft, who, having fallen in love with
her from seeing her portraits, which were sent all over the world,
had left his father’s kingdom that he might have the pleasure of
beholding her and speaking to her. Enchanted at meeting her thus
alone, he addressed her with all the respect and politeness
imaginable. Having remarked, after paying her the usual
compliments, that she was very melancholy, he said to her, “I cannot
understand, madam, how a person so beautiful as you are can be so
unhappy as you appear; for, although I can boast of having seen an
infinite number of beautiful people, I can say with truth that I have
never seen one whose beauty could be compared with yours.”
“You are pleased to say so, sir,” replied the Princess, and there she
stopped.
“Beauty,” continued Riquet, “is so great an advantage, that it
ought to take the place of every other, and, possessed of it, I see
nothing that can have power to afflict one.”
“I would rather,” said the Princess, “be as ugly as you are, and
have intelligence, than possess the beauty I do, and be so stupid as
I am.”
“There is no greater proof of intelligence, madam, than the belief
that we have it not; it is the nature of that gift, that the more we
have, the more we believe ourselves to be without it.”
“I do not know how that may be,” said the Princess, “but I know
well enough that I am very stupid, and that is the cause of the grief
that is killing me.”
“If that is all that troubles you, madam, I can easily put an end to
your sorrow.”
“And how would you do that?” said the Princess.
“I have the power, madam,” said Riquet with the Tuft, “to give as
much intelligence as it is possible to possess, to the person whom I
love best; as you, madam, are that person, it will depend entirely
upon yourself, whether or not you become gifted with this amount of
intelligence, provided that you are willing to marry me.”
 The Princess was struck dumb with astonishment, and replied not
a word.
“I see,” said Riquet with the Tuft, “that this proposal troubles you,
and I am not surprised, but I will give you a full year to consider it.”
The Princess had so little sense, and at the same time was so
anxious to have a great deal, that she thought the end of that year
would never come; so she at once accepted the offer that was made
her. She had no sooner promised Riquet with the Tuft that she would
marry him that day twelve months, than she felt herself quite
another person.
She found she was able to say whatever she pleased, with a
readiness past belief, and of saying it in a clever, but easy and
natural manner. She immediately began a sprightly and well-
sustained conversation with Riquet with the Tuft, and was so brilliant
in her talk, that Riquet with the Tuft began to think he had given her
more wit than he had reserved for himself. On her return to the
palace, the whole Court was puzzled to account for a change so
sudden and extraordinary; for the number of foolish things which
they had been accustomed to hear from her, she now made as many
sensible and exceedingly witty remarks. All the Court was in a state
of joy not to be described. The younger sister alone was not
altogether pleased, for, having lost her superiority over her sister in
the way of intelligence, she now only appeared by her side as a very
unpleasing-looking person.
The King now began to be guided by his elder daughter’s advice,
and at times even held his Council in her apartments. The news of
the change of affairs was spread abroad, and all the young princes
of the neighbouring kingdoms exerted themselves to gain her
affection, and nearly all of them asked her hand in marriage. She
found none of them, however, intelligent enough to please her, and
she listened to all of them, without engaging herself to one.
At length arrived a Prince, so rich and powerful, so clever and so
handsome, that she could not help listening willingly to his
addresses. Her father, having perceived this, told her that he left her
at perfect liberty to choose a husband for herself, and that she had
only to make known her decision. As the more intelligence we
possess, the more difficulty we find in making up our mind on such a
matter as this, she begged her father, after having thanked him, to
allow her time to think about it.
She went, by chance, to walk in the same wood in which she had
met Riquet with the Tuft, in order to meditate more uninterruptedly
over what she had to do. While she was walking, deep in thought,
she heard a dull sound beneath her feet, as of many persons
running to and fro, and busily occupied. Having listened more
attentively, she heard one say, “Bring me that saucepan;” another,
“Give me that kettle;” another, “Put some wood on the fire.” At the
same moment the ground opened, and she saw beneath her what
appeared to be a large kitchen, full of cooks, scullions, and all sorts
of servants necessary for the preparation of a magnificent banquet.
There came forth a band of about twenty to thirty cooks, who went
and established themselves in an avenue of the wood, at a very long
table, and who, each with the larding-pin in his hand and the tail of
his fur cap over his ear, set to work, keeping time to a harmonious
song.
 The Princess, astonished at this sight, asked the men for whom
they were working.
“Madam,” replied the chief among them, “for Prince Riquet with
the Tuft, whose marriage will take place to-morrow.” The Princess,
still more surprised than she was before, and suddenly recollecting
that it was just a twelvemonth from the day on which she had
promised to marry Prince Riquet with the Tuft, was overcome with
trouble and amazement. The reason of her not having remembered
her promise was, that when she made it she had been a very foolish
person, and when she became gifted with the new mind that the
Prince had given her, she had forgotten all her follies.
She had not taken another thirty steps, when Riquet with the Tuft
presented himself before her, gaily and splendidly attired, like a
Prince about to be married. “You see, madam,” said he, “I keep my
word punctually, and I doubt not that you have come thither to keep
yours, and to make me, by the giving of your hand, the happiest of
men.”
“I confess to you, frankly,” answered the Princess, “that I have not
yet made up my mind on that matter, and that I do not think I shall
ever be able to do so in the way you wish.” “You astonish me,
madam,” said Riquet with the Tuft. “I have no doubt I do,” said the
Princess; “and assuredly, had I to deal with a stupid person, with a
man without intelligence, I should feel greatly perplexed. ‘A Princess
is bound by her word,’ he would say to me, ‘and you must marry me,
as you have promised to do so.’ But as the person to whom I speak
is, of all men in the world, the one of greatest sense and
understanding, I am certain he will listen to reason. You know that,
when I was no better than a fool, I nevertheless could not decide to
marry you—how can you expect, now that I have the mind which
you have given me, and which renders me much more difficult to
please than before, that I should take to-day a resolution which I
could not then? If you seriously thought of marrying me, you did
very wrong to take away my stupidity, and so enable me to see more
clearly than I saw then.” “If a man without intelligence,” replied
Riquet with the Tuft, “who reproached you with your breach of
promise, might have a right, as you have just intimated, to be
treated with indulgence, why would you, madam, that I should
receive less consideration in a matter which affects the entire
happiness of my life? Is it reasonable that persons of intellect should
be in a worse position than those that have none? Can you assert
this—you who have so much, and who so earnestly desired to
possess it? But let us come to the point, if you please. Setting aside
my ugliness, is there anything in me that displeases you? Are you
dissatisfied with my birth, my understanding, my temper, or my
manners?”
“Not in the least,” replied the Princess; “I admire in you everything
you have mentioned.”
“If that is so,” rejoined Riquet with the Tuft, “I shall soon be
happy, as you have it in your power to make me the most pleasing
looking of men.”
“How can that be done?” asked the Princess.
“It can be done,” said Riquet with the Tuft, “if you love me
sufficiently to wish that it should be. And, in order, madam, that you
should have no doubt about it, know that the same fairy, who, on
the day I was born, endowed me with the power to give intelligence
to the person I chose, gave you also the power to render handsome
the man you should love, and on whom you should wish to bestow
this favour.”
“If such be the fact,” said the Princess, “I wish, with all my heart,
that you should become the handsomest and most lovable Prince in
the world, and I bestow the gift on you to the fullest extent in my
power.”
The Princess had no sooner pronounced these words than Riquet
with the Tuft appeared to her eyes, of all men in the world, the
handsomest, the best made, and most attractive she had ever seen.
There are some who assert that it was not the spell of the fairy, but
love alone that caused the metamorphosis. They say that the
Princess, having reflected on the perseverance of her lover, on his
prudence, and on all the good qualities of his heart and mind, no
longer saw the deformity of his body, or the ugliness of his features;
that his hump appeared to her nothing more than a good-natured
shrug of his shoulders, and that instead of noticing, as she had
done, how badly he limped, she saw in him only a certain lounging
air, which charmed her. They say also that his eyes, which squinted,
only seemed to her the more brilliant for this; and that the
crookedness of his glance was to her merely expressive of his great
love; and, finally, that his great red nose had in it, to her mind,
something martial and heroic. However this may be, the Princess
promised on the spot to marry him, provided he obtained the
consent of the King, her father. The King, having learned that his
daughter entertained a great regard for Riquet with the Tuft, whom
he knew also to be a very clever and wise Prince, received him with
pleasure as his son-in-law. The wedding took place the next
morning, as Riquet with the Tuft had foreseen, and according to the
orders which he had given a long time before.

No beauty, no talent, has power above

Some indefinite charm discern’d only by love.

“That is delightful, but it is much too short,” said Titania smilingly.

“It is better too short than too long,” answered Oberon, “but
perhaps the pretty little story-teller has another one for us?”
“If your Majesties wish it,” replied the dainty creature.
“Let it be a longer one this time,” said Titania, “and let it be
another tale of true love, please.”
The French Fay considered for a moment, and then said, as if to
herself, “I do know another story of true love rewarded after strange
adventures, but I’m afraid it will be too long for his Majesty’s taste.”
“This one is for me,” said Titania, turning smilingly to the King,
“and my Oberon need not listen if he does not wish to.”
 “Be it as my Queen wishes,” said Oberon, who was really excited
by the promise of hearing of strange adventures.
Then there was a sort of dainty rustling as of the breeze toying
with the summer leaves while all the fairies about the circle settled
comfortably down to listen to the long story which the French Fay
named
 The Benevolent Frog
There was once a King who for many years had been engaged in a
war with his neighbours; a great number of battles had been fought,
and at last the enemy laid siege to his capital. The King, fearing for
the safety of the Queen, begged her to retire to a fortified castle,
which he himself had never visited but once. The Queen
endeavoured, with many prayers and tears, to persuade him to allow
her to remain beside him and to share his fate, and it was with loud
cries of grief that she was put into her chariot by the King to be
driven away. He ordered his guards, however, to accompany her, and
promised to steal away when possible to visit her. He tried to
comfort her with this hope, although he knew that there was little
chance of fulfilling it, for the castle stood a long distance off,
surrounded by a thick forest, and only those who were well
acquainted with the roads could possibly find their way to it.
The Queen parted from her husband, broken-hearted at leaving
him exposed to the dangers of war; she travelled by easy stages, in
case the fatigue of so long a journey should make her ill; at last she
reached the castle, feeling low-spirited and distressed. When
sufficiently rested, she walked about the surrounding country, but
found nothing to interest her or divert her thoughts. She saw only
far-spreading desert tracts on either side, which gave her more pain
than pleasure to look upon; sadly she gazed around her, exclaiming
at intervals, “What a contrast between this place and that in which I
have lived all my life! If I stay here long I shall die! To whom have I
to talk in these solitudes? With whom can I share my troubles? What
have I done to the King that he should banish me? He wishes me, it
seems, to feel the full bitterness of our separation, by exiling me to
this miserable castle.”
Thus she lamented; and although the King wrote daily to her, and
sent her good news of the progress of the siege, she grew more and
more unhappy, and at last determined that she would return to him.
Knowing, however, that the officers who were in attendance upon
her had received orders not to take her back, unless the King sent a
special messenger, she kept her design secret, but ordered a small
chariot to be built for her, in which there was only room for one,
saying that she should like sometimes to accompany the hunt. She
drove herself, and followed so closely on the hounds, that the
huntsmen were left behind; by this means she had sole command of
her chariot, and could get away whenever she liked. Her only
difficulty was her ignorance of the roads that traversed the forest;
but she trusted to the kindness of Providence to bring her safely
through it. She gave word that there was to be a great hunt, and
that she wished everybody to be there; she herself would go in her
chariot, and each was to follow a different route, that there might be
no possibility of escape for the wild beasts. Everything was done
according to her orders. The young Queen, feeling sure that she
should soon see her husband again, dressed herself as becomingly
as possible; her hat was covered with feathers of different colours,
the front of her dress lavishly trimmed with precious stones, and her
beauty, which was of no ordinary kind, made her seem, when so
adorned, a second Diana.
While everybody was occupied with the pleasures of the hunt, she
gave rein to her horses, encouraged them with voice and whip, and
soon their quickened pace became a gallop; then, taking the bit
between their teeth, they flew along at such a speed, that the
chariot seemed borne by the winds, and the eye could scarcely
follow it. Too late the poor Queen repented of her rashness: “What
could I have been thinking of?” she said. “How could I have
imagined that I should be able to control such wild and fiery horses?
Alas! what will become of me? What would the King do if he knew
the great danger I am in, he who loves me so dearly, and who only
sent me away that I might be in greater safety! This is my gratitude
for his tender care!” The air resounded with her piteous
lamentations; she invoked Heaven, she called the fairies to her
assistance, but it seemed that all the powers had abandoned her.
The chariot was overthrown; she had not sufficient strength to jump
quickly enough to the ground, and her foot was caught between the
wheel and the axle-tree; it was only by a miracle she was saved.

She remained stretched on the ground at the foot of a tree; her

heart scarcely beat, she could not speak, and her face was covered
with blood. She lay thus for a long time; when at last she opened
her eyes, she saw, standing near her, a woman of gigantic stature,
clothed only in a lion’s skin, with bare arms and legs, her hair tied up
with the dried skin of a snake, the head of which dangled over her
shoulders; in her hand was a club made of stone, which served her
as a walking-stick, and a quiver full of arrows was fastened to her
side. When the Queen caught sight of this extraordinary figure, she
felt sure that she was dead, for she did not think it was possible that
she could be alive after such a terrible accident, and she said in a
low voice to herself, “I am not surprised that it is so difficult to
resolve to die, since what is to be seen in the other world is so
frightful.” The giantess, who overheard her words, could not help
laughing at the Queen’s idea that she was dead. “Take courage,” she
said to her, “for know that you are still among the living; but your
fate is none the less sad. I am the Fairy Lioness, whose dwelling is
near here; you must come and live with me.” The Queen looked
sorrowfully at her, and said, “If you will be good enough, Madam
Lioness, to take me back to my castle, and tell the King what ransom
you demand, he loves me so dearly, that he will not refuse you even
the half of his kingdom.” “No,” replied the giantess, “I am rich
enough, but for some time past my lonely life has seemed dull to
me; you are intelligent, and will be able perhaps to amuse me.” As
she finished speaking, she took the form of a lioness, and placing
the Queen on her back, she carried her to the depths of her cave,
and there rubbed her with a spirit which quickly healed the Queen’s
wounds. But what surprise and misery for the Queen to find herself
in this dreadful abode! It was only reached by ten thousand steps,
which led down to the centre of the earth; there was no light but
that shed by a number of tall lamps, which were reflected in a lake
of quicksilver. This lake was covered with monsters, each hideous
enough to have frightened a less timid queen; there were owls,
screech-owls, ravens, and other birds of ill omen, filling the air with
discordant sounds; in the distance could be seen rising a mountain
whence flowed the sluggish waters of a stream composed of all the
tears shed by unhappy lovers, from the reservoirs of their sad loves.
The trees were bare of leaves and fruit, the ground covered with
marigolds, briars, and nettles.
The food corresponded to the climate of this miserable country;
for a few dried roots, some horse-chestnuts, and thorn-apples, were
all that was provided by the Fairy Lioness to appease the hunger of
those who fell into her hands.
As soon as the Queen was well enough to begin work, the fairy
told her she could build herself a hut, as she was going to remain
with her for the rest of her life. On hearing this, the Queen could no
longer restrain her tears: “Alas, what have I done to you,” she cried,
“that you should keep me here? If my death, which I feel is near,
would give you pleasure, I pray you, kill me, it is all the kindness I
dare hope from you; but do not condemn me to pass a long and
melancholy life apart from my husband.”
The Lioness only scoffed at her, and told her that the best thing
she could do was to dry her tears, and try to please her; that if she
acted otherwise, she would be the most miserable person in the
world.
“What must I do then,” replied the Queen, “to soften your heart?”
“I am fond of fly-pasties,” said the Lioness. “You must find means of
procuring a sufficient number of flies to make me a large and sweet-
tasting one.” “But,” said the Queen, “I see no flies here, and even
were there any, it is not light enough to catch them; and if I were to
catch some, I have never in my life made pastry, so that you are
giving me orders which it is impossible for me to execute.” “No
matter,” said the pitiless Lioness; “that which I wish to have, I will
have.”
The Queen made no reply: she thought to herself, in spite of the
cruel fairy, that she had but one life to lose, and in the condition in
which she then was, what was there to fear in death? Instead,
therefore, of going in search of flies, she sat herself down under a
yew tree, and began to weep and complain: “Ah, my dear husband,
what grief will be yours, when you go to the castle to fetch me, and
find I am not there; you will think that I am dead, or faithless, and I
would rather that you should mourn the loss of my life, than that of
my love; perhaps someone will find the remains of my chariot in the
forest, and all the ornaments which I took with me to please you;
and when you see these, you will no longer doubt that death has
taken me; and how can I tell that you will not give to another the
heart’s love which you have shared with me? But, at least, I shall not
have the pain of knowing this, since I am not to return to the world.”
She would have continued communing thus with herself for a long
time, if she had not been interrupted by the dismal croaking of a
raven above her head. She lifted her eyes, and by the feeble light
saw a large raven with a frog in its bill, and about to swallow it.
“Although I see no help at hand for myself,” she said, “I will not let
this poor frog perish if I can save it; it suffers as much in its way, as
I do in mine, although our conditions are so different,” and picking
up the first stick she could find, she made the raven drop its prey.
The frog fell to the ground, where it lay for a time half-stunned, but
finally recovering its froggish senses, it began to speak, and said:
“Beautiful Queen, you are the first benevolent person that I have
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