Note: Intro -- Contents -- Angiogenesis: An Ever-Challenging Research Field -- Acknowledgment -- References -- Part I: Angiogenesis During Embryonic Development -- Chapter 1: Emergence of Endothelial Cells During Vascular Development -- 1.1 Introduction -- 1.2 Vasculogenesis -- 1.3 Hemangioblast -- 1.4 Remodeling of the Primary Capillary Plexus into Arteries and Veins -- 1.5 Role of Hemodynamic Forces in Remodeling -- 1.6 Guidance of Capillaries by Endothelial Tip Cells -- 1.7 Circulating Endothelial Cells in the Embryo -- 1.8 Perspectives -- References -- Chapter 2: Lymphatic Vascular Morphogenesis -- 2.1 Early Steps of Lymphatic Vascular Development -- 2.1.1 Lymphatic Endothelial Cell Specification -- 2.1.2 Lymphatic Vessel Sprouting from the Veins -- 2.1.3 Separation of Lymphatic and Blood Vasculatures -- 2.1.4 Non-venous Origins of Lymphatic Vasculature -- 2.2 Lymphatic Vessel Remodelling -- 2.2.1 Sprouting and Growth of Lymphatic Vessels -- 2.2.2 Regulation of Lymphatic Endothelial Cell-Cell Junctions -- 2.2.3 Valve Morphogenesis -- 2.2.4 Smooth Muscle Cells Recruitment to Collecting Lymphatic Vessels -- 2.3 Lymphatic Vasculature and Diseases -- 2.3.1 Lymphoedema -- 2.3.2 Inflammation -- 2.3.3 Tumour Metastasis -- 2.3.4 Lipid Absorption -- 2.4 Concluding Remarks -- References -- Part II: The Physiological Angiogenic Signal: Cellular and Molecular Mechanisms -- Chapter 3: Finding New Partnerships: The Function of Individual Extracellular Receptor Domains in Angiogenic Signalling by VEGF Receptors -- 3.1 Biology of VEGF Family Growth Factors and Their Receptors -- 3.1.1 Introduction to VEGF -- 3.1.2 Structure-Function Relationship of VEGF and VEGF Receptors -- 3.1.2.1 Receptor Specificity of VEGFs -- 3.1.2.2 Structural Analysis of VEGF Binding to VEGFR-1, VEGFR-2 and VEGFR-3 -- 3.1.2.3 Activation of VEGF Receptors. , 3.2 VEGFR-2 as Part of a Signalling Platform -- 3.2.1 Neuropilins (NRPs) -- 3.2.2 Ephrin-B2 -- 3.2.3 VE-Cadherin -- 3.2.4 Dopamine Receptor D2 -- 3.2.5 CD146 -- 3.2.6 CD44 -- 3.3 Extracellular Components of the VEGF/VEGFR Signalling Cascade as Targets for Therapy and Functional Inhibition -- 3.3.1 VEGF/VEGFRs in Disease -- 3.3.2 VEGF/VEGFRs as Targets in Therapeutic Inhibition -- 3.3.2.1 VEGF-Neutralising Agents -- 3.3.2.2 Anti-VEGFR-1 Agents -- 3.3.2.3 Anti-VEGFR-2 D23 Agents -- 3.3.2.4 Anti-VEGFR-2 D4-7 Agents -- 3.3.3 Limitations to VEGF/VEGFR Targeted Therapy -- 3.3.4 Outlook and Conclusions -- References -- Chapter 4: Wnt/Frizzled Signaling in the Vasculature -- 4.1 Introduction -- 4.1.1 Wnt Signal Transduction -- 4.1.1.1 The Canonical Pathway: Wnt/β-Catenin -- 4.1.1.2 The Planar Cell Polarity Pathway -- 4.1.1.3 The Calcium-Mediated Pathway -- 4.1.2 Wnt Inhibitors and Modulators -- 4.1.3 Atypical Receptors Kinases -- 4.2 Role of the Wnt/Frizzled in Vascular Development -- 4.2.1 Evidence of Wnt/Fzd Expression and Signaling in Endothelial Cells -- 4.2.2 Placental Development -- 4.2.3 Postnatal Retinal Angiogenesis -- 4.2.4 Brain Vasculature -- 4.3 Role of Wnt Regulation in Vascular Pathology -- 4.3.1 Choroidal Neovascularization and Oxygen-Induced Retinopathy -- 4.3.2 Wound Healing -- 4.3.3 Hind Limb and Cardiac Ischemia -- 4.4 Conclusion -- 4.5 Online Databases -- References -- Chapter 5: BMP9, BMP10, and ALK1: An Emerging Vascular Signaling Pathway with Therapeutic Applications -- 5.1 Bone Morphogenetic Proteins (BMPs) -- 5.2 BMP9/BMP10/ALK1 Signaling Complex -- 5.3 The Role of BMP9 and BMP10 in Vascular Development -- 5.3.1 Knowledge from Human Vascular Diseases -- 5.3.2 Knowledge from Animal Models: Mice and Zebrafish -- 5.3.2.1 Mice -- 5.3.2.2 Zebrafish -- 5.3.3 In Vitro Roles of BMP9 and BMP10 in Endothelial Cells. , 5.4 Therapeutic Applications of the BMP9/BMP10/ALK1 Signaling Pathway -- 5.4.1 HHT -- 5.4.2 BMP9, BMP10, and ALK1 as Biomarkers in Cancer -- 5.4.3 Therapeutic Applications of the BMP9/BMP10/ALK1 Signaling Pathway in Tumor Angiogenesis -- 5.4.3.1 ALK1 Extracellular Domain (ALK1 ECD) -- 5.4.3.2 Anti-ALK1 Antibody (PF-03446962) -- 5.4.3.3 Anti-endoglin Antibody (TRC105) -- 5.5 Conclusions and Perspectives -- References -- Chapter 6: Apelin Signaling in Retinal Angiogenesis -- 6.1 Apelin Signaling -- 6.1.1 Receptor Discovery and Isolation of the Endogenous Ligand -- 6.1.2 Multiple Active Ligands and Receptor Heterodimers -- 6.1.3 Gene Transcription and Mode of Signaling -- 6.1.4 Physiological Functions of Apelin Signaling -- 6.2 The Retina -- 6.2.1 Anatomy and Development -- 6.2.2 Astrocyte: The Key Mediator of Neuron/Endothelial Cell Interactions -- 6.2.3 Developmental Patterning of Retinal Vessels -- 6.2.4 Subpopulations of Endothelial Cells -- 6.3 Apelin Signaling and Formation of Retinal Vessels -- 6.3.1 Apelin: A Bona Fide Angiogenic Factor -- 6.3.2 Vascular Phenotype of Apelin or APJ Gene Invalidation -- 6.3.3 Temporal Expression of Apelin Signaling Coincides with the Angiogenic Phase -- 6.3.4 Apelin Receptor Gene: An Early Marker of the Venous Phenotype -- 6.3.5 Receptor and Ligand Gene as Potential Markers of Tip or Stalk Phenotype -- 6.3.6 Apelin Signaling as a Linker Between VEGF-Secreting Astrocytes and Proliferating Stalk Cells -- 6.3.7 Apelin Signaling Regulates LIF Secretion and Controls Astrocyte Maturation -- 6.4 Apelin Signaling and Pathological Retinal Angiogenesis -- 6.4.1 The Retinopathy of Prematurity -- 6.4.2 Diabetic Retinopathy -- 6.4.3 Telangiectatic Vessels -- 6.5 Clinical Implications -- References -- Chapter 7: Emerging Role of the Two Related Basic Helix-Loop-Helix Proteins TAL1 and LYL1 in Angiogenesis -- 7.1 Introduction. , 7.2 Properties of LYL1 and TAL1 -- 7.3 Hematopoietic Functions of Tal1, Lyl1, and Lmo2 -- 7.4 Tal1 and Lmo2 Are Required for Cardiovascular Development -- 7.5 TAL1 Activity Is Required in the Early Steps of Angiogenesis -- 7.5.1 TAL1 and LMO2 Initiate Tubulogenesis Through VE-Cadherin Upregulation -- 7.5.2 TAL1-LMO2 Complexes Controls Angiopoietin-2 Expression -- 7.6 LYL1 Is Required for the Maturation of New Blood Vessels -- 7.6.1 Lyl1 Deficiency Leads to Increased Angiogenic Responses -- 7.6.2 LYL1 Contributes to Vessel Maturation and Stabilization -- 7.7 Coordinated Activity of TAL1 and LYL1 to Regulate Angiogenic Processes -- References -- Part III: Hypoxia, Ischemia and Angiogenesis -- Chapter 8: Hypoxia and Extracellular Matrix Remodeling -- 8.1 Hypoxia Induction of Angiogenesis -- 8.2 Establishment of the Vascular BM -- 8.3 Extracellular Matrix Proteolytic Degradation -- 8.4 Regulation of Hypoxia-Induced Growth Factor Sequestration in the Extracellular Matrix -- 8.5 Matricellular Proteins -- 8.5.1 Group A Thrombospondins -- 8.5.2 Group B Thrombospondins -- 8.6 Conclusion -- References -- Chapter 9: Sphingosine-1-Phosphate in Hypoxic Signaling -- 9.1 Hypoxia Significance and Impact on Clinical Outcome -- 9.2 The Hypoxia-Inducible Factors -- 9.3 Sphingosine 1-Phosphate Metabolism in Cancer -- 9.4 Sphingosine 1-Phosphate Signaling in Hypoxia -- 9.5 Sphingosine 1-Phosphate Signaling as a Target for Anti- hypoxic Strategy -- 9.6 Concluding Remarks -- References -- Chapter 10: Reciprocal Crosstalk Between Angiogenesis and Metabolism -- 10.1 Regulation of Angiogenesis by Oxygen and Metabolism -- 10.1.1 PHDs and HIF: The Molecular Players of Angiogenesis Are Regulated by Oxygen and Metabolic Intermediates -- 10.1.2 Modulators of HIF and PHDs by Nonhypoxic Stimuli -- 10.1.2.1 TCA Cycle and Other Metabolic Intermediates. , 10.1.2.2 Reactive Oxygen Species -- 10.1.3 Modulation of Angiogenesis by Metabolic Regulators -- 10.2 EC Metabolism Impacts Vessel Sprouting -- 10.2.1 EC Survival and Functions Are Dependent on Glycolysis -- 10.2.2 Metabolic Changes During Vascular Sprouting -- 10.3 Regulation of Metabolism by Angiogenesis -- Bibliography -- Chapter 11: Endothelial Progenitor Cells and Cardiovascular Ischemic Diseases: Characterization, Functions, and Potential Clinical Applications -- 11.1 Introduction -- 11.2 Cultured EPC -- 11.3 Recruitment of EPCs to the Ischemic Tissue -- 11.3.1 CXCL12/CXCR4 -- 11.3.2 Integrins and Selectins -- 11.3.3 Hemostatic Partners, Thrombospondin, and Thrombin Interaction with EPCs -- 11.3.4 Other Factors -- 11.4 Mechanisms of EPC-Related Effects on Postischemic Revascularization -- 11.4.1 Differentiation into Endothelial Cells -- 11.4.2 Paracrine Effects -- 11.4.3 Interaction with the Host Environment -- 11.5 EPCs as Diagnostic and Prognostic Tools -- 11.5.1 EPCs as Biomarkers of Cardiovascular Diseases -- 11.5.1.1 EPCs and Cardiovascular Risk Factors -- 11.5.1.2 EPCs and the Prevalence of CVDs -- 11.5.2 Are EPCs a Useful Prognostic Factor for Cardiovascular Diseases? -- 11.6 EPCs as Therapeutic Tools -- 11.6.1 Adult Stem/Progenitor Cells -- 11.6.2 Alternative Sources of EPCs -- 11.6.2.1 Embryonic Stem Cells (ESCs) -- 11.6.2.2 Induced Pluripotent Stem Cells (iPSCs) -- 11.6.2.3 Local Source of Stem/Progenitor Cells -- 11.7 Conclusion -- References -- Part IV: Tumor Angiogenesis -- Chapter 12: Endothelial Cell Reactions to Oxygen: Implications for Cancer -- 12.1 Overview of Oxygen-Mediated Pathways -- 12.2 Hypoxia-Inducible Factors Mediate Cellular Oxygen Signaling -- 12.3 The Function of Prolyl Hydroxylase Domain Proteins and Factor Inhibiting HIF as Oxygen Sensors. , 12.4 Role of Oxygen Signaling in Physiological and Pathophysiological Angiogenesis.