Comprehensive and current
Useful for physicians and scientists
Covers coronary vasculature from embryonic origins to senescence
Ischemic heart disease is the leading cause of morbidity and mortality in the developed world. The high metabolism and oxygen demand of the cardiac myocardium depends on both a high blood flow and a rich capillary density. For this reason, the growth of the coronary vasculature is vital, not only in early development, but also in the adult faced with various stresses. Novel technologies have enabled the discovery of the molecular mechanisms underlying the growth and assembly coronary vessels, and this volume covers the hierarchy of the coronary vasculature from its embryonic origins through its postnatal growth, adulthood, and senescence. Chapters address normal coronary development, coronary anomalies and their possible underlying developmental errors, coronary vessel adaptations to exercise training, aging, hypoxia, myocardial ischemia, and cardiac hypertrophy.


This comprehensive overview of current research in coronary vessels and myocardial perfusion was written by Dr. Robert J. Tomanek, Emeritus Professor of Anatomy and Cell Biology at the University of Iowa. The book reviews, discusses, and integrates findings from various areas of coronary vasculature research, and as a result, will be a valuable reference source for cardiovascular scientists and physicians for many years to come

1 General Concepts of Blood Vessel Formation and Remodeling ....................... 1
Introduction ............................................................................................................. 1
Progenitor Cells ...................................................................................................... 1
Embryonic Life ................................................................................................... 1
Postnatal Life ...................................................................................................... 4
Formation of the Primary Capillary Plexus (Vasculogenesis) ................................ 5
Cell Recruitment and Assembly .......................................................................... 5
VEGF VEGFR and the Vasculogenic Cascade .................................................. 5
Fibroblast Growth Factors .................................................................................. 6
Other Key Growth Factors .................................................................................. 7
Integrins and Other Adhesion Molecules ............................................................ 7
Suppressors of Vasculogenesis............................................................................ 7
Branching and Fusion (Angiogenesis) .................................................................... 7
Branches Are Formed by Two Distinct Processes:
Sprouting and Intussusception ............................................................................ 8
Increases in Lumen Diameter ............................................................................. 10
Assembly of the Vascular Hierarchy ....................................................................... 10
Recruitment and Assembly of Pericytes and Smooth Muscle Cells ................... 10
Specification of Arterial and Venous Vessels ...................................................... 11
Remodeling ............................................................................................................. 13
Remodeling During Development ...................................................................... 14
Remodeling in the Adult ..................................................................................... 14
Primary Stimuli for Vascular Growth and Remodeling .......................................... 15
Mechanical Forces .............................................................................................. 15
Hypoxia ............................................................................................................... 16
Vascular Integrity .................................................................................................... 17
Cell Cell Junctions ............................................................................................. 17
Extracellular Matrix ............................................................................................ 17
Pericytes and the Endothelium ............................................................................ 17
References ............................................................................................................... 18
2 Prenatal Coronary Morphogenesis ..................................................................... 25
Introduction ............................................................................................................. 25
Proepicardium ......................................................................................................... 25
Origin of Proepicardium ..................................................................................... 25
Specification of Proepicardial Cells .................................................................... 26
Epicardium .............................................................................................................. 27
Proepicardial Migration and Epicardial Formation ............................................ 27
Regulation of Epicardial Formation .................................................................... 27
xii Contents
Epicardial Myocardial Signaling ....................................................................... 28
Epithelial Mesenchymal Transition and Cell Fate ............................................. 28
Progenitor Cell Migration and the Subepicardium ............................................. 29
Coronary Cell Lineages and Differentiation ........................................................... 30
Coronary Endothelial Cells ................................................................................. 30
Blood Islands and EDPCs ................................................................................... 31
Coronary Smooth Muscle Cells .......................................................................... 31
Fibroblasts and Pericytes .................................................................................... 32
Establishing the Primary Coronary Plexus ............................................................. 32
The Growth Pattern ............................................................................................. 32
Relationship of Coronary Tubulogenesis and Extracellular Matrix ................... 32
Hypoxia Is an Initiator of Tubulogenesis ............................................................ 33
Multiple Growth Factors Regulate Tubulogenesis ............................................. 33
VEGF Family Members Play Key Roles ............................................................ 34
FGFs and Hedgehog Signaling ........................................................................... 34
FGFs and VEGFs Cooperate in Tubulogenesis .................................................. 35
Other Key Molecules for Tubulogenesis ............................................................ 35
Formation of the Coronary Ostia and Onset of Coronary Circulation .................... 35
Vascular Tube Ingrowth into the Aorta ............................................................... 35
Signals for Coronary Ostial and Stem Formation ............................................... 36
VSMC Recruitment and Assembly ..................................................................... 37
Assembly of the Coronary Arterial Tree ............................................................. 38
Development of the Arterial Wall ....................................................................... 38
Formation of Coronary Veins and Lymphatics ....................................................... 38
Coronary Veins .................................................................................................... 38
Lymphogenesis in the Heart ................................................................................ 38
Coronary Development in Humans ........................................................................ 39
Early Development ............................................................................................. 39
Later Development .............................................................................................. 40
References ............................................................................................................... 41
3 Postnatal Coronary Morphogenesis and Growth .............................................. 47
Introduction ............................................................................................................. 47
Methods for Quantitative Assessment of Vessel Growth .................................... 47
Capillary Growth .................................................................................................... 48
Early Postnatal Growth ....................................................................................... 48
Later Postnatal Growth ....................................................................................... 48
Accelerated Myocardial Growth ......................................................................... 49
Capillary Arteriolar and Venular Domains.......................................................... 50
Possible Mechanisms Regulating Postnatal Capillary Growth ........................... 51
Arterial and Arteriolar Growth ................................................................................ 52
Early Rapid Growth of Main Coronary Arteries ................................................. 52
Arterial Growth and Blood Flow ........................................................................ 52
Degenerative Changes in Arteries During Postnatal Growth ............................. 52
Possible Mechanisms Underlying Degenerative Changes .................................. 53
Arteriolar Postnatal Growth ................................................................................ 53
Factors that Regulate Development of the Coronary Arteriolar
and Arterial Hierarchy ......................................................................................... 53
Coronary Blood Flow, O2 Consumption, and Ventricular Function ................... 54
Adaptations to Enhanced Pressure Overload ...................................................... 54
Coronary Collaterals ........................................................................................... 55
References ............................................................................................................... 55
Contents xiii
4 Structure Function of the Coronary Hierarchy ................................................ 59
Introduction ............................................................................................................. 59
Histology and Cell Biology of Coronary Vessels ................................................... 59
The Three Tunics of Arteries and Arterioles ....................................................... 59
Capillaries and Venules ....................................................................................... 61
Distribution and Branching of Arteries in Humans ................................................ 62
Right and Left Artery Dominance ....................................................................... 62
The Major Coronary Arteries .............................................................................. 63
Branching Patterns .............................................................................................. 64
Arterial Hierarchy ................................................................................................... 65
Innervation and Adrenergic Receptors .................................................................... 66
Regulation of Coronary Flow ................................................................................. 66
Distribution of Coronary Resistance ................................................................... 66
Metabolic Regulation .......................................................................................... 67
Myogenic Control ............................................................................................... 68
Effects of Flow and Shear Stress on Coronary Vasodilation .............................. 68
Extravascular Resistance .................................................................................... 68
Neural Control and Coronary Responses ............................................................ 69
Parasympathetic Control ..................................................................................... 71
Coronary Venous System ........................................................................................ 71
Coronary Venous Valves ..................................................................................... 72
Venous Anastomoses ........................................................................................... 72
Smaller (Thebesian) Cardiac Venous System ..................................................... 72
Vasa Vasorum .......................................................................................................... 72
Capillaries ............................................................................................................... 73
Collateral Circulation .............................................................................................. 74
Remodeling of a Native Collateral ..................................................................... 74
Cardiac Lymphatic Vessels ..................................................................................... 76
References ............................................................................................................... 76
5 Historical Perspectives .......................................................................................... 83
Introduction ............................................................................................................. 83
Historical Figures of the Renaissance ..................................................................... 83
Leonardo da Vinci (1452 1519) ......................................................................... 83
Andreas Vesalius (1514 1564) ........................................................................... 83
William Harvey (1578 1657) ............................................................................. 85
Marcello Malpighi (1628 1694) ......................................................................... 85
Richard Lower (1631 1691) ............................................................................... 85
Raymond Vieussens (1641 1716) ...................................................................... 85
Progress in Specific Areas ....................................................................................... 85
Vessels of Thebesius: Nutrition of the Heart ...................................................... 85
Coronary Anastomoses ....................................................................................... 86
Coronary Blood Flow ......................................................................................... 86
Ischemia and Myocardial Infarction ................................................................... 88
Angina Pectoris ................................................................................................... 89
Atherosclerosis .................................................................................................... 90
The Twentieth Century ............................................................................................ 90
Four Giants of the First 50 Years ........................................................................ 91
Advances: 1900 1950 ......................................................................................... 92
Advances: 1951 1970 ......................................................................................... 93
The Coronary System: Progress Delayed ............................................................... 97
References ............................................................................................................... 97
xiv Contents
6 Coronary Anomalies ............................................................................................. 101
Introduction ............................................................................................................. 101
Significance of Coronary Anomalies .................................................................. 101
Chapter Objectives .............................................................................................. 101
Classification of Coronary Anomalies in Human Hearts ........................................ 102
Anomalies of Aortic or Pulmonary Origin .............................................................. 102
Anomalous Origin from the Opposite Sinus of Valsalva .................................... 102
Origin from Pulmonary Artery ............................................................................ 104
Single Coronary Ostium ......................................................................................... 106
Coronary Fistulas .................................................................................................... 106
Coronary Anomalies Involving the Coronary Sinus ............................................... 106
Intrinsic Coronary Anomalies ................................................................................. 106
Myocardial Bridging ........................................................................................... 106
Coronary Artery Atresia ...................................................................................... 108
Coronary Hypoplasia .......................................................................................... 108
Coronary Aneurysms .......................................................................................... 108
Congenital Coronary Anomalies Associated with Congenital
Heart Malformations ............................................................................................... 109
Persistent Truncus Arteriosus .............................................................................. 109
Transposition of the Great Arteries ..................................................................... 110
Tetralogy of Fallot ............................................................................................... 111
Double Outlet Ventricle ...................................................................................... 111
Univentricular Heart ........................................................................................... 111
Possible Mechanisms Underlying Various Coronary Anomalies ....................... 111
Anomalous Aortic and Pulmonary Artery Origin ............................................... 111
Dependence on Growth Factors .......................................................................... 112
A Role for Hypoxia ............................................................................................. 112
Neural Crest Cells ............................................................................................... 113
Gap Junction Protein ........................................................................................... 113
Other Contributors to Coronary Anomalies ........................................................ 113
Coronary Anomalies and Sudden Death ................................................................. 113
Physical Exertion and the Risk of Sudden Cardiac Death .................................. 114
SCD in Athletes................................................................................................... 115
Coronary Abnormalities in Congenital Diseases .................................................... 116
Cyanotic Congenital Heart Disease .................................................................... 116
Noncompaction of the Ventricular Myocardium ................................................ 116
References ............................................................................................................... 116
7 Aging ...................................................................................................................... 123
Introduction ............................................................................................................. 123
Vascular Aging and Disease ................................................................................ 123
Cellular Senescence ............................................................................................ 123
Common Vascular Changes During Aging ............................................................. 124
Aging and Endothelial Dysfunction .................................................................... 124
Arterial Aging ..................................................................................................... 124
Coronary Artery Characteristics in the Very Elderly ....................................... 125
Microvascular Alterations ................................................................................... 125
Structural Changes in Coronary Arteries and Arterioles During Aging ................. 125
Lumen Diameter, Density, and Wall Thickness .................................................. 125
Cellular Changes in the Vascular Wall ................................................................ 126
Neural Changes ................................................................................................... 126
Extracellular Changes ......................................................................................... 127
Contents xv
Functional Changes in Coronary Arteries and Arterioles During Aging ................ 127
Endothelial Dysfunction ..................................................................................... 127
Impairment of Vasodilation ................................................................................. 127
Altered Vasoconstrictor Responses ..................................................................... 129
Changes in the Capillary Bed During Aging .......................................................... 129
Capillary Density is Reduced in Senescence ...................................................... 129
Mechanisms of Impaired Angiogenesis .............................................................. 130
Effects of Aging on Myocardial Perfusion ............................................................. 131
Data from Humans .............................................................................................. 131
Data from Experimental Animals ....................................................................... 131
Hypertension, Atherosclerosis, and Aging .............................................................. 131
Hypertension ....................................................................................................... 131
Effects of Age on Ischemia and Myocardial Infarction .......................................... 133
Ischemia/Reperfusion ......................................................................................... 133
Ischemic Preconditioning .................................................................................... 134
Myocardial Infarction ......................................................................................... 135
Influence of Gender on Aging of Coronary Vessels ................................................ 136
Aging Processes in Myocardium and Coronary Vessels ..................................... 136
Ischemia and Myocardial Infarction ................................................................... 136
References ............................................................................................................... 137
8 Adaptations to Exercise Training ........................................................................ 143
Introduction ............................................................................................................. 143
Coronary Responses During Acute Exercise .......................................................... 143
Vascular Resistance ............................................................................................. 143
Neural and Humoral Factors ............................................................................... 144
Mechanical Factors ............................................................................................. 144
Species Differences ............................................................................................. 144
Maximal Myocardial Perfusion .............................................................................. 144
Artery and Arteriole Adaptations ............................................................................ 145
General Concepts ................................................................................................ 145
Exercise Training Affects Both Vessel Formation and Remodeling ................... 145
Effects of Exercise Training on Vasodilation
of Arteries and Arterioles .................................................................................... 146
ET Reduces Constrictor Responses of Arteries .................................................. 147
Collateral Growth and Adaptations in Humans ...................................................... 148
Collateral Growth and Adaptations in Experimental Animals ................................ 149
Collateral Growth ................................................................................................ 149
Changes in Collateral-Dependent Vessel Function ............................................. 150
Capillary Formation and Remodeling ..................................................................... 151
Studies in Rodents............................................................................................... 152
Studies on Dogs and Swine ................................................................................. 153
ET-Induced Mechanisms of Capillary Growth ................................................... 154
Neovascularization and Blood Flow in Pressure-Overloaded,
Ischemic and Postinfarcted Hearts .......................................................................... 155
Pressure Overload ............................................................................................... 155
Postinfarcted and/or Ischemic Hearts: Studies in Experimental Animals .......... 155
Postinfarcted and/or Ischemic Hearts: Studies in Humans ................................. 156
ET Increases Bone Marrow-Derived Cells ......................................................... 157
Exercise Training Effects on Coronary Artery Disease .......................................... 158
Prevention and Treatment in Humans ................................................................. 158
Data from Experimental Animals ....................................................................... 159
References ............................................................................................................... 160
xvi Contents
9 Hypoxia .................................................................................................................. 167
Introduction ............................................................................................................. 167
Hypoxia and Ischemia ......................................................................................... 167
Continuous and Intermittent Hypoxia ................................................................. 167
Hypoxia-Inducible Factor and Gene Activation ................................................. 167
Hypoxia-Inducible Factor in the Heart ............................................................... 168
Hypoxia and Neovascularization: General Concepts ............................................. 169
HIFs: The Link between Hypoxia and Vascular Growth Factors ....................... 169
Hypoxia and Vessel Sprouting ............................................................................ 170
Effects of Hypoxia on Vascular Cells ................................................................. 170
Mechanisms of Hypoxic Induction of Coronary Artery
Dilation and Coronary Flow ................................................................................... 171
Contributing Signaling Pathways ....................................................................... 171
Prostaglandins ..................................................................................................... 171
Adenosine ........................................................................................................... 172
K+ Channels ........................................................................................................ 172
Nitric Oxide ........................................................................................................ 172
Reactive Oxygen Species .............