Biochemical basis and therapeutic implications of angiogenesis

Preface
Contents
Part I: Molecular Mechanisms in Angiogenesis
	Chapter 1: Endothelial Growth Factor Receptors in Angiogenesis
		1 Introduction: The Signaling Axes Behind Angiogenesis
		2 The VEGF Axis
			2.1 VEGF Structure and Function
				2.1.1 The VEGF Receptors
		3 Co-Receptors
		4 The Role of the Endothelial Growth Factor Receptors in Angiogenesis and Neovascularization
			4.1 The Role of the Endothelial Growth Factor Receptors in Tumorigenesis
				4.1.1 VEGFR-1
				4.1.2 VEGFR-2
				4.1.3 VEGFR-3
				4.1.4 Prognosis
				4.1.5 Metastasis
				4.1.6 Autocrine Signaling
				4.1.7 Therapeutic Applications
			4.2 The Eye
				4.2.1 Therapeutic Applications
			4.3 Pro-angiogenic Therapies
		5 Conclusion
		References
	Chapter 2: The Role of Integrins in Angiogenesis
		1 Introduction
		2 Bidirectional Signaling by Integrins Regulates Cellular Fate
		3 Integrin Binding to Proteolytic Protein Fragments
		4 Crosstalk of Integrins with Other Signaling Pathways
			4.1 Notch Signaling
			4.2 VEGF Signaling
			4.3 TGF-β Signaling
		5 Integrin Inhibition in Tumor Angiogenesis
		6 Integrin Inhibitors in Clinical Development
			6.1 GLPG0187
			6.2 Cilengitide
			6.3 ATN-161
			6.4 DI17E6
		7 Conclusions
		References
	Chapter 3: Toll-Like Receptors in Angiogenesis
		1 Introduction: Toll! Everything Started in Drosophila
		2 Toll-Like Receptors in Mammalians
		3 Angiogenesis: General Remarks
		4 Inflammation-Induced Angiogenesis
		5 Toll-Like Receptors in Inflammation-Induced Angiogenesis
		6 Toll-Like Receptors in Infection-Induced Angiogenesis
		7 Toll-Like Receptors in Tumor Angiogenesis
		8 Endogenous Toll-Like Receptor Ligands in Angiogenesis
		9 Oxidative Stress and Toll-Like Receptor-Dependent Angiogenesis
		10 A Side Glance on NOD Receptors and Angiogenesis
		11 Summary and Therapeutic Perspectives
		References
	Chapter 4: Vascular Stem Cells in Regulation of Angiogenesis
		1 Introduction
		2 Angiogenesis and Stem Cells
			2.1 Circulating Endothelial Progenitor Cells
			2.2 Hematopoietic Stem Cells
			2.3 Mesenchymal Stem Cells
			2.4 Smooth Muscle Progenitor Cells
			2.5 Vascular Pericytes
		3 External Factors Regulate Angiogenesis Process
			3.1 Chemotaxis: Cytokines, Chemokines, and Growth Factors
			3.2 Haptotaxis
			3.3 Mechanotaxis
			3.4 Hypoxia
		4 Signaling Molecules Involved in Angiogenesis
			4.1 Notch and Delta Signaling
			4.2 Hedgehog Signaling
			4.3 MicroRNA
		5 Conclusions and Future Directions
		References
	Chapter 5: Role of Transforming Growth Factor Beta Family in Angiogenesis
		1 TGFβ Molecule Family- Sources, Activation and Regulation of Transcription
			1.1 The TGFβ family
			1.2 TGFβ Sources
			1.3 Synthesis and Activation of TGFβ
			1.4 Regulation of Transcription by TGFβ
			1.5 TGFβ’s Role in Angiogenesis
		2 TGFβ Receptors and Signalling
			2.1 Canonical SMAD Signalling
			2.2 Non-canonical Signalling Pathways
		3 TGFβ and Endothelial Sprouting, Proliferation and Permeability
			3.1 Endothelial Sprouting
			3.2 Endothelial Permeability
			3.3 Endothelial Proliferation and Migration
		4 TGFβ Co-receptors in Angiogenesis
			4.1 Regulation of TGFβ Ligand Access to Co-Receptors
			4.2 TGFβ and Vascular Mural Cells
		5 Pathological Angiogenesis
			5.1 HHT
			5.2 Organ Fibrosis
			5.3 Cancer
		References
	Chapter 6: Angiogenesis-Based Strategy by Hepatocyte Growth Factor for the Treatment of Ischemic Organ Diseases: From Biology to Clinical Trials
		1 Introduction
		2 Biological Aspect for Angiogenic Roles of HGF
			2.1 Molecular Basis for Mitogenic Actions
			2.2 Mechanisms of HGF-Induced EC Motility or Migration
			2.3 Molecular Basis for Morphogenesis
		3 Anti-edematous Mechanisms by HGF
			3.1 Molecular Basis for Barrier Stabilization
			3.2 Anti-inflammation
			3.3 Anti-apoptosis
			3.4 Pericyte Recruitment
		4 Preclinical Evaluation of HGF During PAD
			4.1 Loss of Local HGF Production During Experimental PAD
			4.2 Pre-clinical POC of Recombinant HGF for Treating PAD
			4.3 HGF Naked Plasmid Therapy
			4.4 Alternative Strategy for HGF-Based Angiogenesis in PAD
		5 Therapeutic Angiogenesis in Other Ischemic Organs
			5.1 HGF-Based Angiogenic Treatment for Heart Diseases
			5.2 Cerebrovascular Diseases
			5.3 Lung Emphysema and Other Pulmonary Diseases
		6 Clinical Trials of HGF for the Treatment of Ischemic Diseases
			6.1 Naked Plasmid Containing HGF cDNA (Collategene)
			6.2 VM202
			6.3 Ad-HGF Vector
		7 Summary and Perspective
		References
	Chapter 7: Functions of MicroRNAs in Angiogenesis
		1 Introduction
		2 MiR-16 Family and Angiogenesis
			2.1 MiR-15 and miR-16 and Angiogenesis
			2.2 MiR-195/-497 and Angiogenesis
			2.3 MiR-15/-107 Group and Angiogenesis
		3 MiR-17-92 Custer and Angiogenesis
		4 MiR-126/miR-126* and Angiogenesis
		5 MiR-221/-222 and Angiogenesis
		6 MiR-378 and Angiogenesis
		7 MiR-21 and Angiogenesis
		8 MiR-210 and Angiogenesis
		9 MiR-503/-424 Cluster and Angiogenesis
		10 Other MiRs Related to Angiogenesis
		11 Conclusion
		References
	Chapter 8: Mast Cells in Angiogenesis: The Role of Angiogenic Cytokines
		1 Introduction
		2 Mast Cells and Angiogenesis
		3 Angiogenic Cytokines Involved in Mast Cell Angiogenesis
		4 Therapeutic Approach
		References
Part II: Therapeutic Implications of Angiogenesis in Cancer
	Chapter 9: Therapeutic Implications of  Angiogenesis in Cancer
		1 Introduction
		2 Tumor Angiogenesis
			2.1 Tumor Initiation, Prevascular Phase and Tumor Dormancy
			2.2 Angiogenesis
			2.3 Soluble Factors (Table 9.1)
			2.4 Membrane-Bound Factors
			2.5 Biomechanical Forces
			2.6 Endogenous Inhibitors of Angiogenesis
			2.7 The Angiogenic Switch (AS) (Fig. 9.1)
			2.8 Consequences of the Angiogenic Switch
			2.9 Physiologic Competence of Tumor Blood Vessels
			2.10 Evaluation of Angiogenesis and Prediction of Response to Angiogenic Therapy
			2.11 Clinical Evaluation of Prognostic and Predictive Markers of Angiogenesis
		3 Tumor Lymphangiogenesis
		4 Targeting Angiogenesis
			4.1 FDA Approved Drugs
			4.2 Mechanism of Action of Antiangiogenic Drugs
			4.3 Resistance to Antiangiogenic Drugs
		5 Therapeutic Implications in Different Cancers
			5.1 Colorectal Cancer
				5.1.1 Major Angiogenic Pathways
				5.1.2 Approved and Studied Drugs Targeting Angiogenesis in Colorectal Cancer
				5.1.3 Future Directions
			5.2 Gastric Cancer
				5.2.1 Major Angiogenic Pathways
				5.2.2 Anti- angiogenesis Drugs in Gastric Cancer
				5.2.3 Future Directions
			5.3 Liver Cancer
				5.3.1 Major Angiogenic Pathways
				5.3.2 Drugs Targeting Angiogenesis in HCC and Results of Clinical Trials
				5.3.3 Future Directions
			5.4 Lung Cancer
				5.4.1 Drugs Targeting Angiogenesis in Lung Cancer and Results of Clinical Trials
				5.4.2 Future Directions
			5.5 Breast Cancer
			5.6 Kidney Cancer
				5.6.1 Major Angiogenic Pathways
				5.6.2 Approved Drugs from Clinical Trials
				5.6.3 Future Clinical Trials
			5.7 Ovarian Cancer
			5.8 Brain Tumors
				5.8.1 Major Angiogenic Pathways and Related Chemotherapy/Radiotherapy Resistance
				5.8.2 Pseudoprogression and Angiogenesis:
				5.8.3 Approved Drugs Targeting Angiogenesis
				5.8.4 Future Directions
		6 Conclusion
		References
	Chapter 10: The Role of Angiogenesis in Non-small Cell Lung Cancer Tumor Behavior
		1 Introduction
		2 Effects of Tumor Hypoxia and Clinical Issues
		3 Genetic Polymorphisms Related to Angiogenesis Pathways
		4 Genetic Polymorphisms and Risk of Lung Cancer
		5 Genetic Polymorphisms and Non-small-cell Lung Cancer Prognosis
		6 Current and Future Developments
		References
	Chapter 11: Angiogenesis and Prostate Cancer: Friends or Foes
		1 Introduction
		2 Angiogenesis and Inflammation
		3 Angiogenesis and the Epithelial-Mesenchymal Transition
		4 Prostate Cancer and Angiogenesis: More Than One Alternative
		5 Prostate Cancer and the Microvessel Density Evaluation
		6 Concluding Remarks
		References
Part III: Therapeutic Implications of Angiogenesis in Eye Disorders
	Chapter 12: Angiogenesis-Based Therapies for Eye Diseases
		1 Angiogenesis
		2 Molecular Mechanisms of Angiogenesis
		3 VEGF Signaling
		4 Role of VEGF Receptors in Angiogenesis
		5 Anti-VEGF Therapies
		6 Natural Anti-angiogenic Molecules
		7 Angiogenic Retinal Diseases
			7.1 Age-Related Macular Degeneration (AMD)
				7.1.1 Current Anti-angiogenic Therapies for AMD
				7.1.2 Novel/Experimental Agents
				7.1.3 Gene Therapy
			7.2 Myopic Choroidal Neovascularization
				7.2.1 Current Anti-angiogenic Therapies for mCNV
			7.3 Diabetic Retinopathy (DR)
				7.3.1 Current Anti-angiogenic Therapies for DR
			7.4 Retinal Vein Occlusion (RVO)
				7.4.1 Current Anti-angiogenic Therapies for RVO
		8 Future Directions in Angiogenesis Based Therapies
		9 Conclusions
		References
	Chapter 13: Anti-angiogenesis Therapy in Diabetic Retinopathy
		1 Introduction
		2 Angiogenesis and Diabetic Retinopathy
		3 Anti-VEGF Medications and Clinical Trials
			3.1 Pegaptanib
			3.2 Bevacizumab
			3.3 Ranibizumab
				3.3.1 Pilot Studies
				3.3.2 READ-2 and READ-3 Trials
				3.3.3 RISE and RIDE
				3.3.4 RESOLVE and RESTORE
				3.3.5 DRCR.net PROTOCOL I
				3.3.6 RETAIN
				3.3.7 Ranibizumab for PDR
			3.4 Aflibercept
				3.4.1 Pilot Study
				3.4.2 DA VINCI
				3.4.3 VIVID and VISTA
			3.5 Comparison Trials
		4 Corticosteroids and Clinical Trials
			4.1 Triamcinolone
			4.2 Dexamethasone
			4.3 Fluocinolone
		5 Future Therapies
		6 Conclusions
		References
Part IV: Therapeutic Implications of Angiogenesis in Cardiovascular Disorders and Peripheral Vascular Disease
	Chapter 14: Therapeutic Angiogenesis, Cell Therapy and Peripheral Vascular Disease
		1 Frequency and Clinical Manifestations of PAD
		2 Angiogenesis
		3 Therapeutic Angiogenesis and Peripheral Arterial Disease (PAD)
		4 Gene and Cell Approaches to Induce Therapeutic Angiogenesis
			4.1 Nucleic Acid Delivery in Gene Transfer
		5 Gene Therapy Mediated Therapeutic Angiogenesis in Critical Limb Ischemia (CLI)
			5.1 Vascular Endothelial Growth Factor Gene Therapy
			5.2 Fibroblast Growth Factor (FGF)
			5.3 Hepatocyte Growth Factor (HGF)
			5.4 Hypoxia Induced Factor-1 Alpha (HIF-1α)
			5.5 Overview/Summary of Gene Therapy for Angiogenesis
		6 Cell Therapy for Therapeutic Angiogenesis
			6.1 Different Modes of Delivery Cell Therapy
			6.2 Clinical Trials of Cell Therapy in Patients with CLI
			6.3 Overview of Cell Therapy Trials for Therapeutic Angiogenesis
		References
	Chapter 15: Cell-Based Therapy in Ischemic Heart Disease
		1 Background
		2 Methodological Aspects of Clinical Cell-Based Therapy
			2.1 Cell Populations
			2.2 Routes of Cell Delivery
		3 Randomized-Controlled Evidence on Cell-Based Therapy for Ischemic Heart Disease
			3.1 Acute Myocardial Infarction
			3.2 Ischemic Cardiomyopathy
			3.3 Refractory Angina
		4 Challenges and Limitations in Clinical Cell-Based Therapies
			4.1 Beside-to-Bench: Modeling of Ischemia
			4.2 Ideal Cell Population
			4.3 Selection of Study Endpoints
			4.4 Timing and Dosing of Cell Transfer
			4.5 Local Retention of Viable Cells
		5 Perspective
			5.1 Cell Modification
			5.2 Supportive Biomaterials
			5.3 Combined Approaches
		References
	Chapter 16: Angiogenesis and Atherosclerosis
		1 Introduction: Angiogenesis in Health and Disease
		2 Mechanism of New Vessel Formation
		3 Angiogenesis in Atherosclerosis: A Historical Perspective
		4 Determinants of Atherosclerotic Plaque Angiogenesis: Role of Hypoxia, Oxidative Stress and Endothelial Dysfunction
		5 Plaque Neovascularization and Its Consequences
		6 The Angiogenesis Paradox: To Be or Not to Be?
		7 Understanding Different Angiogenesis Pathways: Collateral Arteriogenesis vis-à-vis Plaque Angiogenesis
		8 Specificity and Heterogeneity in the Expression of Angiogenesis
		9 Therapeutic Angiogenesis: Promises and Problems
		10 Summary
		References
	Chapter 17: microRNAs, Angiogenesis and Atherosclerosis
		1 Introduction
		2 microRNA Biogenesis
		3 Atherosclerosis-Associated microRNA
			3.1 miR-126
			3.2 miR-143/145
			3.3 miR-17-92 Cluster
			3.4 miR-155
			3.5 miR-21
			3.6 miR-29 Family
		4 Circulating microRNAs
			4.1 Circulating microRNAs as Prognostic Biomarkers of Coronary Artery Disease
			4.2 Circulating microRNAs as Prognostic Biomarkers of Acute Myocardial Infarction
		5 MicroRNA-Based Therapeutic Strategies
		6 Conclusion
		References
	Chapter 18: Trials of Angiogenesis Therapy in Patients with Ischemic Heart Disease
		1 Introduction
		2 Human Trials of Cardiovascular Protein Therapy
			2.1 Fibroblast Growth Factor (FGF)
			2.2 Vascular Endothelial Growth Factor (VEGF)
			2.3 Granulocyte Colony Stimulating Factor (G-CSF)
		3 Granulocyte Monocyte Colony Stimulating Factor (GM-CSF)
		4 Human Trials Using Other Agents that Promote Angiogenesis
		5 Human Trials of Gene Therapy
			5.1 VEGF Gene Trials
			5.2 FGF Gene Trials
			5.3 Other Gene Therapy Trials
		6 Conclusion
		References
Part V: Therapeutic Implications of Angiogenesis in Miscellaneous Disease States
	Chapter 19: Perspectives in New Advances in Retinal Neovascularization Pathogenesis and Therapeutic Approaches
		1 Introduction
		2 Ocular Neovascularization and Related Eye Diseases
			2.1 Age-Related Macular Degeneration
			2.2 Proliferative Diabetic Retinopathy and Diabetic Macula Edema
			2.3 Retinopathy of Prematurity
		3 Angiogenesis
		4 Mammalian Ocular Angiogenesis and the Role of VEGF in Mammalian Retina
		5 Current Therapies for Ocular Neovascularization
			5.1 Vascular Endothelial Growth Factor Inhibitors (Anti-VEGFs)
			5.2 Photodynamic Therapy (PDT) and Laser Photocoagulation
			5.3 Limitations
		6 Emerging Therapies to Treat Ocular Neovascularization
			6.1 Endostatin
			6.2 Pigment Epithelium-Derived Factor
			6.3 Platelet-Derived Growth Factor Inhibitors
			6.4 Integrin Receptor Blocker
			6.5 Thrombospondin-1 (TSP)
			6.6 Peroxisome Proliferator-Activated Receptor Alpha (PPARα) Agonist
			6.7 Wnt Pathway Blocker
			6.8 Corticosteroid Implants
			6.9 Complement Cascade Inhibitors
			6.10 Other Small Molecule Inhibitors
		7 Conclusion and Perspective
		References
	Chapter 20: The Role of Sex Steroids in Angiogenesis
		1 Introduction
		2 Sex Steroids and Angiogenesis: Basic Mechanisms
			2.1 Overview of the Actions of Sex Steroid
			2.2 Estrogen-Mediated Neovascularization
			2.3 Estrogen and Genomic Pathways of Regulation
			2.4 Estrogen and Non-genomic Rapid Signaling
			2.5 Estrogens and Endothelial Cells
				2.5.1 Estrogen and Endothelial Cell Attachment, Migration and Tubule Formation
				2.5.2 Estrogen and Endothelial Cell Proliferation
			2.6 Estrogen and Endothelial Progenitor Cells (EPCs)
			2.7 Androgens and Angiogenesis
			2.8 Androgens and Progenitor Cells
			2.9 Sex Specificity of Steroid Action
		3 Sex Steroids and Angiogenesis: Role in Health and Disease
			3.1 Estrogen and Menstruation and Angiogenesis
			3.2 Sex Steroids and Tumor Angiogenesis
				3.2.1 Estrogen and Tumor Angiogenesis
				3.2.2 Testosterone and Tumor Angiogenesis
		4 Conclusion
		References
	Chapter 21: Brain Angiogenesis After Stroke
		1 Introduction
		2 Brain Angiogenesis After Stroke
			2.1 Growth Factors for Brain Angiogenesis
				2.1.1 Vascular Endothelial Growth Factor
				2.1.2 Fibroblast Growth Factor-2 (FGF-2/bFGF)
				2.1.3 Platelet-Derived Growth Factor-Beta
				2.1.4 Transforming Growth Factor-Beta
			2.2 Biphasic Responses of Angiogenic Factors After Stroke
				2.2.1 Matrix Metalloproteinase
				2.2.2 High-Mobility Group Box 1
				2.2.3 c-Jun N-Terminal Kinase (JNK)
			2.3 Endothelial Progenitor Cell in Brain Angiogenesis
		3 Neurovascular and Oligovascular Signaling for Brain Angiogenesis
			3.1 Neurovascular Damage in the Acute Phase
			3.2 Neurovascular Repair in the Chronic Phase
			3.3 Cell–Cell Trophic Coupling in White Matter
		4 Therapeutic Implication
			4.1 Combination Therapy with VEGF
			4.2 Cell Junction Molecule
			4.3 Cell-Based Therapy
		5 Conclusion
		References
	Chapter 22: Stimulated Microgravity and Induction of Angiogenesis; A New Perspective in Wound Healing
		1 Introduction
		2 Wound Healing
		3 Wound Inflammation, Chronic Inflammation Switch Over to Tumor
		4 Wound Care and Management: A Chronology
		5 Proposing Microgravity as a Technique for Wound Healing by Promoting Angiogenesis
		6 Microgravity Perturbs Vascularization in Wound Milieu?
		7 Experimental Approach
			7.1 Cell Viability Under Simulated Microgravity
			7.2 Migration of Endothelial Cells Under Simulated Microgravity
			7.3 Prediction of Microgravity Stimulated Genes Involved in Angiogenesis
			7.4 Microgravity Activates Endothelium
			7.5 Effect of Microgravity on Endothelial Cells in Relation to Wound Healing
		8 Consolidation of the Outcome of Cell Biology and Omics Results and Future Direction
		References
	Chapter 23: Role of Skeletal Muscle Angiogenesis in Peripheral Artery Disease
		1 Introduction
		2 General Characteristics of Angiogenesis
		3 Pathophysiology and Therapy of Peripheral Arterial Disease
		4 Mechanisms of Skeletal Muscle Angiogenesis
		5 Conclusions
		References
Index