The Vasculome

Opis

The Vasculome: From Many, One introduces the fundamental bases of the “unity in diversity of the Vasculome, from the coming together of various cell lineages during development, to its deceptively simple solution for architectural design: the efficient interplay of a few types of building blocks supporting key similar functions throughout the body and their highly specialized functional local variations. Specific examples are included to illustrate how the Vasculome is integral to the function and malfunction of different organs, such as the brain or the kidney.

Each section is preceded by an introductory summary that will give a high level unified view of the key concepts illustrated in the various chapters in that section.

Brings together leading experts who present the latest biomedical thinking about the vasculature from the integrative perspective of the Vasculome
Challenges traditional real and perceived boundaries within vascular research areas and stimulates new fundamental thinking and medical explorations
Creates the bases for translating the integrative Vasculome concept into improved fundamental and clinical assessment and management of local and systemic contributions of the vasculature in health and disease

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Front Cover 2
THE VASCULOME 3
THE VASCULOME: FROM MANY, ONE 5
Copyright 6
Contents 7
Contributors 13
Preamble 19
- “THE VASCULOME: FROM MANY, ONE” CONCEPT ZORINA S. GALIS 19
- PART I. THE ARCHITECTURAL DESIGN OF THE VASCULOME: BASIS FOR SYSTEM-WIDE FUNCTIONAL UNITY AND LOCAL DIVERSITY 20
  - Section 1. The endothelium as the key unifying principle of the vasculome. Basis for endothelial systemic unity and for eng ... 20
  - Section 2. Vasculome's key building blocks—beyond the endothelium 22
  - Section 3. Putting it all together: vasculome integration across body scales and within tissues 23
- PART II. INVESTIGATING THE VASCULOME: CONTEXT-DRIVEN METHODS, USES, AND LIMITATIONS 24
  - Section 1. Experimental and computational studies of the vasculome 24

Front Cover 2
THE VASCULOME 3
THE VASCULOME: FROM MANY, ONE 5
Copyright 6
Contents 7
Contributors 13
Preamble 19
- “THE VASCULOME: FROM MANY, ONE” CONCEPT ZORINA S. GALIS 19
- PART I. THE ARCHITECTURAL DESIGN OF THE VASCULOME: BASIS FOR SYSTEM-WIDE FUNCTIONAL UNITY AND LOCAL DIVERSITY 20
  - Section 1. The endothelium as the key unifying principle of the vasculome. Basis for endothelial systemic unity and for eng ... 20
  - Section 2. Vasculome's key building blocks—beyond the endothelium 22
  - Section 3. Putting it all together: vasculome integration across body scales and within tissues 23
- PART II. INVESTIGATING THE VASCULOME: CONTEXT-DRIVEN METHODS, USES, AND LIMITATIONS 24
  - Section 1. Experimental and computational studies of the vasculome 24
  - Section 2. Realizing the promise of new high-content technologies 26
- PART III. VASCULOME DYNAMICS: IN HEALTH AND IN SICKNESS 26
  - Section 1. Cooperating during development and organogenesis to create vasculome diversity 26
  - Section 2. Physiological and pathological remodeling of the vasculome 27
- PART IV. THE VASCULOME AS PERPETRATOR AND VICTIM IN LOCAL AND SYSTEMIC DISEASES 28
- PART V. LOOKING FORWARD TOWARD “PRECISION HEALTH” FOR THE VASCULOME 30
- ACKNOWLEDGMENTS 31
- References 31
Acknowledgment 33
List of abbreviations 35
I - The architectural design of the vasculome: basis for system-wide functional unity and local diversity 53
- 1 - The endothelium: key unifying principle of the vasculome. Basis for systemic unity and for engineering of local s ... 55
  - 1 - Development of, and environmental impact on, endothelial cell diversity 57
    - Introduction 57
    - Diversity of endothelial cell types 57
      - Arterial–venous specification 58
      - Hematopoietic and mesenchymal transition 59
      - Lymphatic specification 59
    - Endothelial cell diversity within adult organs 59
    - Impact of environmental factors on endothelial cell specification 60
      - Hemodynamic forces 60
      - Metabolic substrates 62
      - Hypoxia 62
    - Epigenetic and noncoding RNA regulation of endothelial cell phenotype 62
    - Summary and conclusions 63
    - References 64
  - 2 - Endothelial cell heterogeneity and plasticity in health and disease—new insights from single-cell studies 69
    - Introduction 69
    - Endothelial cell heterogeneity and plasticity 69
      - Diversification of endothelial cells 69
      - Differentiation of endothelial cells into other cell types 70
    - Angiogenic EC phenotypes 71
    - EC metabolic heterogeneity 72
      - EC metabolism during angiogenesis 72
      - Metabolic gene signatures of ECs 73
    - EC heterogeneity in tissue repair 74
      - Tissue repair 74
      - Vessel regeneration 74
    - EC heterogeneity in cancer 75
    - References 77
    - Perspectives and therapeutic implications 77
  - 2 Vasculome's key building blocks—beyond the endothelium 81
    - 3 - The remarkable diversity of vascular smooth muscle in development and disease: a paradigm for mesenchymal cell ... 83
      - Introduction 83
      - The vascular system is a developmental mosaic 83
      - Assembly of the vessel wall in development 84
      - VSMC differentiation, phenotypic switching, and reprogramming 85
      - Self-organization guides artery wall development 85
      - Positional identity and VSMC diversity 85
      - VSMC reprogramming to multiple mesenchymal cell types 86
      - Role of Krüppel-like factor 4 in VSMC reprogramming 87
      - VSMC single-cell transcriptomes and VSMC reprogramming 87
      - Vascular smooth muscle clonal expansions in vivo 88
      - VSMC single-cell transcriptomes and embryonic origins 88
      - Does VSMC reprogramming extend “the vasculome” beyond the vascular system? 89
      - SMC diversity: one genome, many epigenomes 89
      - VSMCs—a paradigm for mesenchymal cell types 89
      - References 90
      - Acknowledgments 90
    - 4 - Smooth muscle diversity in the vascular system 97
      - Introduction 97
        
        Definition of the problem: diversity within the vascular system 97
        
        Gene programs 97
        
        Vascular smooth muscle functional diversity 98
      - Vascular smooth muscle cell diversity: contractile properties 98
        
        Myh11 98
        
        Smoothelin 99
        
        Broader smooth muscle gene program 99
      - Vascular smooth muscle cell diversity in vasomotor control and signaling networks 99
        
        Introduction 99
        
        Splice variant isoforms of the MP regulatory subunit code for variable presence of a C-terminal leucine zipper motif 100
        
        Leucine zipper motifs and role of variable expression in vasodilator responses 100
        
        Activation of this vasodilator pathway by reactive oxygen species 101
        
        Diversity in other signaling pathways controlling VSM tone 101
      - Alternative splicing to rewire signaling networks 102
      - Newer methodologies for the study of smooth muscle diversity 102
        
        Single cell isolation and RNA sequencing 102
        
        Bioinformatics 103
      - Acknowledgment 103
      - References 103
      - Conclusion 103
    - 5 - Resident vascular immune cells in health and atherosclerotic disease 109
      - Macrophages 109
        
        Adventitial resident tissue macrophages of the aorta 110
        
        Intimal resident macrophages: MAC-AIR 111
        
        Macrophages in the diseased vessel wall 111
      - Granulocytes 112
      - Dendritic cells 113
        
        Dendritic cell populations in arteries 113
        
        Function of dendritic cells in arteries 114
      - CD4+ and CD8+ T cells 114
        
        CD8+ T cells 115
        
        CD4+ T helper cells 115
      - Other T cell subsets 115
        
        γδT cells 115
        
        Natural killer T cells 116
      - B cells 116
      - Other lymphoid cells 116
      - Conclusion 117
      - References 118
    - 6 - Perivascular adipose tissue: friend or foe? 123
      - Introduction 123
      - PVAT vascular functions 123
      - Perivascular adipose tissue implications in pathology 124
      - Conclusion 125
      - References 125
    - 7 - Major vascular ECM components, differential distribution supporting structure, and functions of the vasculome 129
      - Structure and function of the vasculome 129
        
        ECM organization in different vascular beds 129
        
        Primary functions of different vascular beds 129
      - Major vascular ECM proteins 131
        
        Collagens 131
        
        Elastin and elastic fibers 132
        
        Proteoglycans and glycosaminoglycans 132
        
        Other glycoproteins 134
      - The ECM and its interactions with cells 134
        
        Substrate for cells and modulator of cell phenotype 134
        
        Control transport and availability of signaling molecules 134
      - References 135
      - Conclusions 135
    - 3 - Putting it all together: vasculome integration across body scales and within tissues 139
      - 8 - Out to the tissues: the arterial side (arteries, arterioles—development, structure, functions, and pathologies) 141
        
        The arterial wall: development, structure, and function 141
        
        Tunica intima 142
        
        Tunica media 143
        
        Tunica adventitia 144
        
        Tissue-specific heterogeneity in the arterial system 144
        
        Introduction 141
        
        The arterial system 141
        
        Arterial pathologies 145
        
        Supravalvular aortic stenosis and Williams–Beuren syndrome 145
        
        Atherosclerosis and restenosis 145
        
        Pulmonary hypertension 146
        
        Aneurysms 146
        
        Coronavirus disease 2019 147
        
        Conclusion 147
        
        Acknowledgments 148
        
        References 148
      - 9 - Capillary diversity: endothelial cell specializations to meet tissue metabolic needs 151
        
        Attributes of capillary endothelial cells 151
        
        Introduction 151
        
        Maintenance and expansion of capillary networks 152
        
        Endothelial control of nutrient delivery 154
        
        Glucose uptake 154
        
        Fatty acid uptake 155
        
        Release of angiocrine factors to support tissue physiology 155
        
        Endothelial cell role in immune surveillance 157
        
        Indicators of tissue-specific endothelial cell plasticity? 157
        
        Consequences of compromised endothelial cell performance 158
        
        References 158
        
        Conclusions 158
        
        Acknowledgments 158
      - 10 - The neurovascular unit and blood–CNS barriers in health and disease 163
        
        CNS angiogenesis and BBB/BRB development 163
        
        Brain 163
        
        Retina 166
        
        The neurovascular unit and the blood–CNS barrier in the healthy state 163
        
        Vascular basement membrane and CNS vascular barrier maturation 167
        
        Retina 167
        
        Brain 167
        
        The neurovascular unit and blood–CNS barriers in neurological and ocular diseases 168
        
        Stroke 168
        
        Multiple sclerosis 170
        
        Retinal pathologies 172
        
        References 173
      - 11 - Lymphatic biology and medicine 179
        
        Lymphatic vasculature 179
        
        Introduction 179
        
        Lymphangiogenesis 180
        
        Lymphatic sprouting 180
        
        LEC specification 180
        
        Lymphatic maturation 181
        
        Lymphedema 181
        
        Risk factors 182
        
        Inflammation in lymphedema 182
        
        Lymphatic remodeling in lymphedema 184
        
        Pathological conditions with lymphatic defects 184
        
        Obesity 184
        
        Atherosclerosis 185
        
        Solid organ transplant rejection 185
        
        Concluding remarks 186
        
        References 186
      - II- Investigating the vasculome: context-driven methods, uses, and limitations 191
        
        1 - Experimental and computational studies of the vasculome 193
        
        12 - The flow-dependent endotheliome: hemodynamic forces, genetic programs, and functional phenotypes 195
        
        Flow patterns in the human circulation 195
        
        Introduction 195
        
        Unraveling flow-dependent endothelial gene expression and functional phenotypes 196
        
        Modeling human hemodynamic forces in vitro 196
        
        Conclusions and future directions 199
        
        Acknowledgments 199
        
        References 200
        
        13 - Intravital photoacoustic microscopy of microvascular function and oxygen metabolism 203
        
        Multiparametric PAM: the working principles 203
        
        Introduction 203
        
        Intravital PAM of the skin microvasculature 205
        
        Intravital PAM of the dorsal vasculature 206
        
        Intravital PAM of the cerebral microvasculature 206
        
        Frontiers in intravital PAM of the microvasculature 210
        
        Intravital PAM of the microvasculature in other tissues and organs 210
        
        Conclusion 211
        
        References 212
        
        Acknowledgments 212
        
        14 - Systems biology modeling of endothelial cell and macrophage signaling in angiogenesis in human diseases 215
        
        Introduction 215
        
        Computational models of HIF stabilization and HIF-mediated cellular pathways in angiogenesis 215
        
        HIF1α–ROS interaction 216
        
        HIF1α–p53 interaction 216
        
        Regulation of HIF1α by hydroxylases 216
        
        HIF-mediated regulation of pro- and antiangiogenic factors 216
        
        Computational models of growth factor-mediated signaling pathways regulating angiogenesis 216
        
        ANG 218
        
        FGF 218
        
        VEGF 218
        
        Computational multipathway models of endothelial cells and macrophages in angiogenesis 219
        
        Endothelial cells 219
        
        Macrophages 220
        
        Discussion and future perspectives 220
        
        References 222
        
        15 - Simulation of blood flow and oxygen transport in vascular networks 225
        
        Introduction 225
        
        Simulation of blood flow 226
        
        Characteristics of blood flow in the vasculature 226
        
        Calculation of flow rates in microvascular networks 227
        
        Flow estimation with incomplete boundary conditions 227
        
        Simulation of oxygen transport 228
        
        Green's function method 228
        
        Physics of oxygen transport 228
        
        Solution methods 228
        
        Estimation of oxygen boundary conditions 229
        
        Acknowledgments 230
        
        References 230
        
        Discussion 230
        
        16 - Clinical investigations of vascular function 233
        
        Vascular endothelial function 233
        
        Mediators of endothelial function 233
        
        Nitric oxide (NO) 233
        
        Prostaglandins, endothelium-derived hyperpolarizing factor, and other endothelium-derived vasoactive agents 234
        
        Other biomarkers of endothelial function: oxidative stress, ADMA, and endothelial microparticles 235
        
        Endothelial function 233
        
        Clinical assessment of endothelial function 236
        
        Coronary endothelial function 236
        
        Peripheral arterial tonometry 237
        
        Peripheral endothelial function assessments 237
        
        Flow-mediated dilation 237
        
        Clinical implications of endothelial dysfunction 237
        
        Therapy for endothelial dysfunction 238
        
        Arterial stiffness 238
        
        Mechanisms for arterial stiffness 238
        
        Methods for evaluation of arterial elastic properties 238
        
        Determinants of arterial elasticity 239
        
        Arterial stiffness and target organ damage 239
        
        Arterial stiffness and cardiac manifestations 240
        
        Arterial stiffness and renal manifestations 241
        
        Arterial stiffness and the brain 241
        
        Arterial stiffness and prognosis 241
        
        Arterial stiffness as a target for treatment 241
        
        Conclusions 242
        
        Appendix A. Supplementary data 243
        
        References 243
        
        2 - Realizing the promise of new high-content technologies 249
        
        17 - Angiodiversity—A tale retold by comparative transcriptomics 251
        
        Introduction 251
        
        Diverse origins of ECs and various modes of vessel formation 251
        
        Vascular expansion during growth and remodeling angiogenesis 252
        
        Angiogenesis 252
        
        Vasculogenesis 252
        
        Lymphangiogenesis 252
        
        EC fate 252
        
        Discovery of endothelial heterogeneity 253
        
        Structural endothelial features—caveolae versus fenestrae 254
        
        Endothelial heterogeneity and organ-specific vasculature 254
        
        Paracrine VEGF signaling, fenestral biogenesis and maintenance 255
        
        Endothelial specialization in the CNS 255
        
        Exploring the CNS vasculome 257
        
        Building the blood–brain barrier 257
        
        Wnt/β-catenin signaling delineates CNS EC regionalization 258
        
        EC arteriovenous zonation in the CNS 258
        
        Transcriptional analysis of brain ECs reveals new endothelial cell types 259
        
        Profound alterations of EC programs during aging 259
        
        Exploring the kidney vasculome 262
        
        Transcriptomic analysis of embryonic and adult kidney 263
        
        Mining the vascular epigenetic landscape 263
        
        Inventory of the adult kidney vasculature 264
        
        Harnessing in vivo understanding of the vasculature to instruct in vitro tissue generation 265
        
        Metabolic adaption of renal ECs revealed by transcriptomic analysis 265
        
        The renal endothelium 262
        
        Regionalization and specialization of kidney vasculature 262
        
        Where do we go from here? 265
        
        References 267
        
        Acknowledgments 267

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