The Vasculome : From Many, One

The Vasculome: From Many, One highlights the unique integrative nature of the body-wide distributed vascular system. The book 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. Recognized experts are invited to contribute to this shared perspective of the Vasculome: from classic names and other outstanding researchers challenging the boundaries of fundamental understanding, to academic physicians ready to translate the latest scientific and technological advancements to holistically assess the contribution of the Vasculome to human health and disease, with the ultimate goal to improve prevention and treatment of a wide variety of medical conditions, and combining traditional and state of the art knowledge presented in a novel way. The Vasculome: FROM MANY, ONE Copyright Contributors Companion website List of abbreviations Preamble “The vasculome: from many, one” concept Zorina S. Galis Part I. The architectural design of the vasculome: basis for system-wide functional unity and local diversity Section 1. The endothelium as the key unifying principle of the vasculome. Basis for endothelial systemic unity and for eng ... Section 2. Vasculome's key building blocks—beyond the endothelium Section 3. Putting it all together: vasculome integration across body scales and within tissues Part II. Investigating the vasculome: context-driven methods, uses, and limitations Section 1. Experimental and computational studies of the vasculome Section 2. Realizing the promise of new high-content technologies Part III. Vasculome dynamics: in health and in sickness Section 1. Cooperating during development and organogenesis to create vasculome diversity Section 2. Physiological and pathological remodeling of the vasculome Part IV. The vasculome as perpetrator and victim in local and systemic diseases Part V. Looking forward toward “precision health” for the vasculome Acknowledgments References Acknowledgment 1. Development of, and environmental impact on, endothelial cell diversity Introduction Diversity of endothelial cell types Arterial–venous specification Hematopoietic and mesenchymal transition Lymphatic specification Endothelial cell diversity within adult organs Impact of environmental factors on endothelial cell specification Hemodynamic forces Metabolic substrates Hypoxia Epigenetic and noncoding RNA regulation of endothelial cell phenotype Summary and conclusions References 2. Endothelial cell heterogeneity and plasticity in health and disease—new insights from single-cell studies Introduction Endothelial cell heterogeneity and plasticity Diversification of endothelial cells Differentiation of endothelial cells into other cell types Angiogenic EC phenotypes EC metabolic heterogeneity EC metabolism during angiogenesis Metabolic gene signatures of ECs EC heterogeneity in tissue repair Vessel regeneration Tissue repair EC heterogeneity in cancer Perspectives and therapeutic implications References 3. The remarkable diversity of vascular smooth muscle in development and disease: a paradigm for mesenchymal cell types Introduction The vascular system is a developmental mosaic Assembly of the vessel wall in development Self-organization guides artery wall development Positional identity and VSMC diversity VSMC differentiation, phenotypic switching, and reprogramming VSMC reprogramming to multiple mesenchymal cell types Role of Krüppel-like factor 4 in VSMC reprogramming VSMC single-cell transcriptomes and VSMC reprogramming VSMC single-cell transcriptomes and embryonic origins Vascular smooth muscle clonal expansions in vivo SMC diversity: one genome, many epigenomes VSMCs—a paradigm for mesenchymal cell types Does VSMC reprogramming extend “the vasculome” beyond the vascular system? Acknowledgments References 4. Smooth muscle diversity in the vascular system Introduction Definition of the problem: diversity within the vascular system Gene programs Vascular smooth muscle functional diversity Vascular smooth muscle cell diversity: contractile properties Myh11 Smoothelin Broader smooth muscle gene program Vascular smooth muscle cell diversity in vasomotor control and signaling networks Introduction Splice variant isoforms of the MP regulatory subunit code for variable presence of a C-terminal leucine zipper motif Leucine zipper motifs and role of variable expression in vasodilator responses Activation of this vasodilator pathway by reactive oxygen species Diversity in other signaling pathways controlling VSM tone Alternative splicing to rewire signaling networks Newer methodologies for the study of smooth muscle diversity Single cell isolation and RNA sequencing Bioinformatics Conclusion Acknowledgment References 5. Resident vascular immune cells in health and atherosclerotic disease Macrophages Adventitial resident tissue macrophages of the aorta Intimal resident macrophages: MAC-AIR Macrophages in the diseased vessel wall Granulocytes Dendritic cells Dendritic cell populations in arteries Function of dendritic cells in arteries CD4+ and CD8+ T cells CD4+ T helper cells CD8+ T cells Other T cell subsets γδT cells Natural killer T cells B cells Other lymphoid cells Conclusion References 6. Perivascular adipose tissue: friend or foe? Introduction PVAT vascular functions Perivascular adipose tissue implications in pathology Conclusion References 7. Major vascular ECM components, differential distribution supporting structure, and functions of the vasculome Structure and function of the vasculome ECM organization in different vascular beds Primary functions of different vascular beds Major vascular ECM proteins Collagens Elastin and elastic fibers Proteoglycans and glycosaminoglycans Other glycoproteins The ECM and its interactions with cells Substrate for cells and modulator of cell phenotype Control transport and availability of signaling molecules Conclusions References 8. Out to the tissues: the arterial side (arteries, arterioles—development, structure, functions, and pathologies) Introduction The arterial system The arterial wall: development, structure, and function Tunica intima Tunica media Tunica adventitia Tissue-specific heterogeneity in the arterial system Arterial pathologies Supravalvular aortic stenosis and Williams–Beuren syndrome Atherosclerosis and restenosis Pulmonary hypertension Aneurysms Coronavirus disease 2019 Conclusion Acknowledgments References 9. Capillary diversity: endothelial cell specializations to meet tissue metabolic needs Introduction Attributes of capillary endothelial cells Maintenance and expansion of capillary networks Endothelial control of nutrient delivery Glucose uptake Fatty acid uptake Release of angiocrine factors to support tissue physiology Endothelial cell role in immune surveillance Indicators of tissue-specific endothelial cell plasticity? Consequences of compromised endothelial cell performance Conclusions Acknowledgments References 10. The neurovascular unit and blood–CNS barriers in health and disease The neurovascular unit and the blood–CNS barrier in the healthy state CNS angiogenesis and BBB/BRB development Brain Retina Vascular basement membrane and CNS vascular barrier maturation Brain Retina The neurovascular unit and blood–CNS barriers in neurological and ocular diseases Stroke Multiple sclerosis Retinal pathologies References 11. Lymphatic biology and medicine Introduction Lymphatic vasculature Lymphangiogenesis LEC specification Lymphatic sprouting Lymphatic maturation Lymphedema Risk factors Inflammation in lymphedema Lymphatic remodeling in lymphedema Pathological conditions with lymphatic defects Obesity Atherosclerosis Solid organ transplant rejection Concluding remarks References 12. The flow-dependent endotheliome: hemodynamic forces, genetic programs, and functional phenotypes Introduction Flow patterns in the human circulation Modeling human hemodynamic forces in vitro Unraveling flow-dependent endothelial gene expression and functional phenotypes Conclusions and future directions Acknowledgments References 13. Intravital photoacoustic microscopy of microvascular function and oxygen metabolism Introduction Multiparametric PAM: the working principles Intravital PAM of the skin microvasculature Intravital PAM of the dorsal vasculature Intravital PAM of the cerebral microvasculature Intravital PAM of the microvasculature in other tissues and organs Frontiers in intravital PAM of the microvasculature Conclusion Acknowledgments References 14. Systems biology modeling of endothelial cell and macrophage signaling in angiogenesis in human diseases Introduction Computational models of HIF stabilization and HIF-mediated cellular pathways in angiogenesis Regulation of HIF1α by hydroxylases HIF1α–ROS interaction HIF1α–p53 interaction HIF-mediated regulation of pro- and antiangiogenic factors Computational models of growth factor-mediated signaling pathways regulating angiogenesis VEGF ANG FGF Computational multipathway models of endothelial cells and macrophages in angiogenesis Endothelial cells Macrophages Discussion and future perspectives References 15. Simulation of blood flow and oxygen transport in vascular networks Introduction Simulation of blood flow Characteristics of blood flow in the vasculature Calculation of flow rates in microvascular networks Flow estimation with incomplete boundary conditions Simulation of oxygen transport Physics of oxygen transport Solution methods Green's function method Estimation of oxygen boundary conditions Discussion Acknowledgments References 16. Clinical investigations of vascular function Vascular endothelial function Endothelial function Mediators of endothelial function Nitric oxide (NO) Prostaglandins, endothelium-derived hyperpolarizing factor, and other endothelium-derived vasoactive agents Other biomarkers of endothelial function: oxidative stress, ADMA, and endothelial microparticles Clinical assessment of endothelial function Coronary endothelial function Peripheral endothelial function assessments Flow-mediated dilation Peripheral arterial tonometry Clinical implications of endothelial dysfunction Therapy for endothelial dysfunction Arterial stiffness Mechanisms for arterial stiffness Methods for evaluation of arterial elastic properties Determinants of arterial elasticity Arterial stiffness and target organ damage Arterial stiffness and cardiac manifestations Arterial stiffness and renal manifestations Arterial stiffness and the brain Arterial stiffness and prognosis Arterial stiffness as a target for treatment Conclusions Appendix A. Supplementary data References 17. Angiodiversity—A tale retold by comparative transcriptomics Introduction Diverse origins of ECs and various modes of vessel formation Vasculogenesis EC fate Angiogenesis Lymphangiogenesis Vascular expansion during growth and remodeling angiogenesis Discovery of endothelial heterogeneity Endothelial heterogeneity and organ-specific vasculature Structural endothelial features—caveolae versus fenestrae Paracrine VEGF signaling, fenestral biogenesis and maintenance Endothelial specialization in the CNS Exploring the CNS vasculome Building the blood–brain barrier Wnt/β-catenin signaling delineates CNS EC regionalization EC arteriovenous zonation in the CNS Profound alterations of EC programs during aging Transcriptional analysis of brain ECs reveals new endothelial cell types The renal endothelium Regionalization and specialization of kidney vasculature Exploring the kidney vasculome Mining the vascular epigenetic landscape Transcriptomic analysis of embryonic and adult kidney Inventory of the adult kidney vasculature Metabolic adaption of renal ECs revealed by transcriptomic analysis Harnessing in vivo understanding of the vasculature to instruct in vitro tissue generation Where do we go from here? Acknowledgments References 18. Using pattern recognition and discriminant analysis of functional perfusion data to create “angioprints” for normal and per ... Introduction Overall experimental design Results Discussion Methods Experimental data Mouse strains Mouse models of experimental angiogenesis Functional fluorescence microangiography Automated pattern recognition and discrete optimization-based classification model for discriminant analysis Image-based pattern recognition algorithm Development of classification rules for prediction of normal and anomalous angiogenic microvasculature Acknowledgments References Further reading 19. Artificial intelligence for the vasculome Introduction Machine learning–based artificial intelligence Types of learning Statistical machine learning algorithms Deep learning The vasculome and the role of machine learning–based AI in its study Conclusion References 20. Vascular development and organogenesis: depots of diversity among conduits of connectivity define the vasculome Introduction Historical perspective of the vasculome concept Vascular development and organogenesis: where it all starts Vascular development and organogenesis: location-dependent crosstalk Circulation-dependent input for local vascular specialization The vasculome: conclusions and future directions Acknowledgments References 21. Normal vascular identity (arteries, veins, and lymphatics) and malformations Introduction Vasculogenesis: arteriovenous differentiation Angiogenesis: sprouting angiogenesis Establishing vascular identity Arteries Veins Lymphatics Vascular malformations Simple malformations Capillary malformations Lymphatic malformations Venous malformations Arteriovenous malformations Combined vascular malformations Malformations of major named vessels Vascular malformations associated with other anomalies Vascular tumors Switching of arterial–venous identity Vein grafts AVF Vascular patches Summary Acknowledgments References 22. Sprouting angiogenesis in vascular and lymphatic development Vascular development Sprouting angiogenesis Vascular endothelial growth factor and regulation of tip cell formation Guidance receptor signaling The Notch directive: tip or stalk? Refinement of sprouting angiogenesis by BMP signals Lymphatic development References 23. Enablers and drivers of vascular remodeling Introduction Brief on vascular mechanics Biological and physiological consequences of mechanics Mechanobiology and SMC phenotype ECM turnover in evolving mechanical states Mechanical homeostasis—an organizing principle Conclusion Appendix 1 Acknowledgments References 24. Extracellular matrix dynamics and contribution to vascular pathologies Atherosclerosis Development of the atherosclerotic plaque How the dynamic ECM influences plaque pathology Proteoglycans bind lipids, signal cell migration, and facilitate collagen fibrillogenesis Fibronectin is increased with shear stress and promotes EC adhesion molecule expression Fibrillar collagens strengthen the fibrous cap, while nonfibrillar collagens and degradation products activate VSMCs and ma ... Elastin and degradation products influence VSMC phenotype Matrix metalloproteinases and plaque rupture Vascular calcification ECM signals for calcification Collagen and fibronectin Elastin degradation products AGE/RAGE, MGP, and osteopontin Matrix stiffness sensing by the cytoskeleton and vascular calcification Arterial stiffening Defining arterial stiffening: causes and consequences Extracellular matrix remodeling in arterial stiffening, the old favorite Collagen VIII in arterial stiffening: an area for future investigation Cellular dysfunction in arterial stiffening, the new favorite Comorbidities associated with arterial stiffening: atherosclerosis and diabetes Sex differences in arterial stiffening: more studies needed Aneurysms Defining aneurysms Aneurysms within the vascular tree Thoracic aortic disease Elastin-contractile unit uncoupling in TAD Marfan syndrome and Loeys–Dietz syndrome Abdominal aortic aneurysms Diabetes and aneurysms Limitations and areas needing further study References 25. Lymphatic vascular anomalies and dysfunction Introduction Lymphatic vascular tumors Kaposiform hemangioendothelioma Lymphangioleiomyomatosis Lymphatic malformations Common or cystic LM Generalized lymphatic anomaly Gorham-Stout disease Channel type LM Lymphatic malformations associated with other vascular malformations or overgrowth syndromes Klippel-Trenaunay Syndrome (KTS) CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and spinal/skeletal anomalies an ... CLAPO syndrome (capillary malformation of the lower lip, lymphatic malformation, asymmetry, and partial or generalized over ... Parkes Weber syndrome Lipedema Primary lymphedema Syndromic lymphedema Lymphedema with visceral involvement Congenital lymphedema Lymphedema praecox Lymphedema tarda Conclusions Acknowledgment References 26. Endothelial dysfunction: basis for many local and systemic conditions Introduction Physiological role of endothelial (vascular) function Mechanisms of endothelial dysfunction Oxidative stress Inflammation Prognostic value of endothelial function and its measurement Determination of endothelial function by intracoronary infusion of acetylcholine and forearm plethysmography Flow-mediated dilation of the brachial artery and finger-pulse plethysmography (ENDO-PAT) Therapeutic prevention of endothelial (vascular) dysfunction Established drugs improving endothelial dysfunction Antioxidant therapy Antiinflammatory therapy Pharmacological targeting of oxidatively impaired eNOS and sGC Nitric oxide and other substitution therapies Conclusions and clinical implications Acknowledgments References 27. The vascular phenotype in hypertension Introduction Vascular function: integration of vascular smooth muscle contraction/relaxation Calcium-dependent mechanisms of vascular smooth muscle contraction Calcium-independent mechanisms of vascular smooth muscle cell contraction Vascular smooth muscle cell relaxation Cytoskeleton components and vascular function Oxidative stress and vascular function in hypertension Vascular functional changes in hypertension Vascular remodeling in hypertension Mechanisms of vascular remodeling in hypertension—role of Ang II The immune system and inflammation—a new paradigm in the vascular phenotype in hypertension Inflammation and the vasculome in hypertension Innate immunity, vascular dysfunction, and hypertension Adaptive immunity, vascular inflammation, and hypertension Perivascular adipose tissue influences vascular function in hypertension PVAT regulation of vascular function in hypertension Vascular aging in hypertension Extracellular matrix components and vascular structural changes with aging Vascular functional changes with aging and hypertension p66Shc, vascular aging, and blood pressure Conclusions Acknowledgments References 28. Functional roles of lymphatics in health and disease Introduction Lymphatics in adipose metabolism and obesity Lymphatics in skin regeneration Lymphatics in the central nervous system Alzheimer's disease Aging Lymphatic function in aqueous drainage and glaucoma Lymphatics in cardiovascular disease Atherosclerosis Myocardial infarction Conclusions Acknowledgments References 29. Extracellular matrix genetics of thoracic and abdominal aortic diseases Thoracic aortic aneurysms predispose to acute aortic dissections Heritable thoracic aortic disease genetics highlights the importance of maintaining an aortic structural component, the ela ... Pathogenic genetic variants that disrupt the extracellular matrix Pathogenic variants that disrupt the SMC contractile unit HTAD genes disrupting TGF-β signaling Sporadic thoracic aortic disease The genetics of abdominal aortic aneurysms The extracellular matrix in genetics of aortic disease Acknowledgments References 30. Peripheral arterial disease (pathophysiology, presentation, prevention/management) Introduction PAD: epidemiology and risk factors Demographic, socioeconomic, and environmental factors Smoking Diabetes Hypertension, dyslipidemia, metabolic syndrome Inflammation Diagnosis and initial evaluation Physiologic assessment and imaging Spectrum of disease Clinical presentations, staging, and natural history Asymptomatic disease Intermittent claudication Chronic Limb-Threatening Ischemia Acute limb ischemia and major adverse limb events Disease patterns and risk factor correlations Pathophysiology and pathobiology Endothelial dysfunction Vascular smooth muscle activation Vascular injury response, restenosis Thrombosis and thromboembolism Diabetes and hyperglycemia Calcification Microvascular disease Disease management Optimal medical therapy, risk reduction, and exercise Revascularization Surveillance Postprocedural considerations and complications PAD therapies in development Vascular regeneration Bioengineered vascular conduits and scaffolds Conclusions References 31. Venous diseases including thromboembolic phenomena Venous thrombogenesis with special emphasis on selectins Venous thrombosis and resolution Leukocyte roles Cellular factors in fibrinolysis, neovascularization, and matrix turnover Animal models for venous research: applicability to clinical venous thrombosis Pre-clinical/basic science models Murine models of venous thrombosis Rat models of venous thrombosis Preclinical/translational models Rabbit models of venous thrombosis Canine model of venous thrombosis Swine deep vein thrombosis model Nonhuman primate models of venous thrombosis Nonhuman primate complete stasis Research reproducibility/comparative pathology/statistical consultation New areas of venous research in thrombogenesis, resolution, and novel approaches for the future Biomarkers Specific clinical scenarios Medical and surgical evolution References 32. Targeting vascular zip codes: from combinatorial selection to drug prototypes Introduction A brief history of phage display In vivo phage display and vascular zip codes Human vascular mapping project Translational/clinical applications Bone Metastasis Targeting Peptidomimetic-11 (BMTP-11) Adipotide Other zip codes Conclusions Conflict of interest statement References 33. Angiosome concept for vascular interventions Introduction General considerations of the angiosome concept Angiosome concept: anatomical and pathophysiological data Anatomy of the distal leg angiosomes Angiosomal SA and their collateral system Primary SA of the distal leg and foot Collateral network surrounding the foot angiosomes Main connections between the foot angiosomes Foot angiosomes as fractal levels of perfusion in the inferior limb Main arterial anatomical variants of the lower leg Pathophysiological data of angiosomal flow Flow compensation during preischemic conditions Postischemic reperfusion stages Functional angiosome Collateral flow reserve and microvascular resistances between angiosomes Clinical implementation of the angiosome model in the current treatment of CLTI Defining angiosome-directed revascularization Technical feasibility of intentional direct revascularization Chronic limb-threatening ischemia and chronic angiosome-threatening ischemia: two competitive or rather complementary notions Current investigation and perspectives for angiosome-targeted revascularization in the treatment of CLTI Summary Acknowledgments References 34. RNA therapies for cardiovascular disease Introduction to RNA therapeutics Antisense oligonucleotides Small interfering RNAs Aptamer-based therapeutics RNA therapeutics in lipid disorders Proprotein convertase subtilisin/kexin type 9 Ongoing clinical trials accessing the therapeutic value of targeting PCSK9 mRNA Angiopoietin-like 3 Ongoing clinical trials accessing the therapeutic value of targeting angiopoietin-like 3 mRNA Apolipoprotein C-III Ongoing clinical trials accessing the therapeutic value of targeting apolipoprotein C-III mRNA Apolipoprotein B Apolipoprotein(a) Ongoing clinical trials accessing the therapeutic value of targeting APO(a) mRNA Emerging RNA therapeutics for cardiac transthyretin amyloidosis Patisiran Revusiran Vutrisiran Inotersen Future perspectives Funding source References 35. The brain vasculome: an integrative model for CNS function and disease Introduction Vasculome modifying factors Genetics Aging Comorbidities Circadian rhythm Cell–Cell interactions Astrocytes Pericytes Vascular smooth muscle cells Levels of vasculome mapping Transcriptome Proteome Secretome Metabolome The functional vasculome Conclusions and future directions Acknowledgments References 36. Vasculome: defining and optimizing vascular health Introduction Pillars of vascular health Assessing ASCVD risk Biomarkers Risk calculators Cardiovascular imaging Carotid intima–media thickness Coronary artery calcium Optimizing vascular health Medications, supplements, vitamins Lifestyle approaches, population health, and public policy Conclusion References 37. The Vasculome provides a body-wide cellular positioning system and functional barometer. The “Vasculature as Common Coordin ... Key requirements for a common coordinate frame (CCF) for the human body Evaluating the vasculature as CCF and road map for the human body CCF will work across scales CCF should be applicable to all (most) body tissues CCF should account for donor differences CCF should be useful and acceptable across specialty domains Practical considerations for using the vasculature as a human body CCF Vasculature as a barometer of functional tissue status and health Parting thoughts Acknowledgments References Index A B C D E F G H I J K L M N O P Q R S T U V W X Y Z 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. Zorina Galis'The Vasculome was named a finalist in the Clinical Medicine category of the American Association of Publishers'2023 PROSE Awards. 2023 PROSE Awards - Winner: Finalist: Clinical Medicine: Association of American Publishers 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