The Vasculome: From Many, One

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
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