CONTENTS -- PREFACE -- Chapter 1 FLOW AND ATHEROSCLEROSIS -- 1. Overview and Clinical Significance -- 1.1. Composition and Progression of Atherosclerotic Plaques -- 1.1.1. Early Lesions -- 1.1.2. Advanced Lesions -- 1.1.3. Outward Remodeling and Plaque Stenosis -- 2. Methods for Studying the Role of Flow in the Pathogenesis of Atherosclerosis -- 2.1. Tools for Studying Biological Responses to Mechanical Stimuli in Vitro -- 2.2. Animal Models of Atherosclerosis and Relation to Flow -- 2.2.1. Genetically-manipulated Mouse Models -- 2.2.2. Mechanical Induction of Stenosis in Animals -- 2.2.3. Larger Animal Models of Atherosclerosis -- 2.3. Flow in Humans and Its Role in Atherosclerosis -- 2.4. Computational Fluid Dynamics -- 2.4.1. Imaging Data for Lesion-specific Geometry -- 2.4.2. Modeling Assumptions -- 3. Wall Shear Stress is a Potent Modulator of Plaque Formation and Localization -- 3.1. Low and Oscillatory Wall Shear Stress Promote Atherosclerotic Plaque Formation -- 3.2. High Wall Shear Stress Protects Arteries from Atherosclerosis -- 3.3. Hemodynamic Parameters Related to Plaque Formation -- 3.4. Wall Shear Stress and Plaque Rupture -- 4. Flow is Not the Only Biomechanical Determinant of Plaque Formation and Disruption -- 4.1. Solid Wall Mechanics and Atherosclerotic Responses to Stretch -- 4.2. Plaque Composition Influences Solid Wall Mechanics and Risk for Rupture -- 4.3. Fluid-solid Interaction Provides Additional Biomechanical Insight into Atherosclerosis -- 5. Current Dilemmas and Future Directions for Atherosclerotic Research -- 5.1. Need for Better Understanding of Plaque Disruption Events -- 5.2. How Do Flow-mediated Mechanisms of Atherogenesis Occur on Human Timescales? -- 5.3. How Much Does Directionality of Flow Contribute to Atherosclerosis? -- 6. Conclusion -- References -- Chapter 2 SHEAR STRESS-MEDIATED SIGNAL TRANSDUCTION.

1. Introduction -- 2. Mechanosignal Transduction: From Molecular Sensors to Cellular Responses -- 3. The Role of Mechanotransduction in Cardiovascular Health and Disease -- 4. The Unique Role of PECAM-1 in Mechanosensing -- 4.1. Forced-induced PECAM-1 Phosphorylation and Mechano-signaling -- 4.2. PECAM-1 as a Mechanosensor -- 4.3. PECAM-1 Kinase in Mechanotransduction -- 5. S-flow-mediated Redox Regulation and Inflammation -- 5.1. TRX and TRX-interacting Protein (TXNIP) -- 5.2. Thiol Regulation and Glutaredoxin -- 6. S-flow Inhibits TNF-α Signaling by Multiple Mechanisms -- 6.1. MAP Kinases in Response to s-flow and TNF-α -- 6.2. S-flow Inhibits PKCζ Signaling in ECs -- 6.3. S-flow Inhibits TNF-α-mediated SHP-2 Phosphatase Activity and MEKK3 Signaling -- 6.4. ERK5 Inhibits TNF-α-mediated JNK Activation -- 7. ERK5 and Shear Stress -- 7.1. s-flow Mediated ERK5 Activation -- 7.2. ERK5 in Diabetes: ERK5-SUMOylation -- 7.2.1. SUMOylation -- 7.2.2. ERK5-SUMOylation -- Acknowledgments -- References -- Chapter 3 ENDOTHELIAL GLYCOCALYX STRUCTURE AND ROLE IN MECHANOTRANSDUCTION -- 1. Introduction -- 2. Structure of the Glycocalyx -- 2.1. Molecular Composition and Organization of the Glycocalyx -- 2.2. Glycocalyx Thickness -- 3. Glycocalyx Role in Mechanotransduction -- 3.1. Biomolecular Response to FSS -- 3.2. Endothelial Cell Remodeling in Response to FSS -- 3.3. Theoretical Models of Mechanotransduction -- 4. Concluding Remarks -- Acknowledgement -- References -- Chapter 4 ROLE OF KRUPPEL-LIKE FACTORS IN SHEAR STRESS-MEDIATED VASOPROTECTION -- 1. Introduction -- 1.1. Kruppel-Like Factors -- 1.2. Kruppel-Like Factor 2 -- 1.3. Regulation of KLF2 by Laminar Shear Stress -- 1.4. Targets of Shear-Stress Induced KLF2 -- 1.4.1. Inflammation and atherogenesis -- 1.4.2. Thrombosis -- 1.4.3. Vascular Development/Maturation/Remodeling -- 1.4.4. Angiogenesis.

1.4.5. Vascular Stress/Injury -- 1.5. KLF2, Shear Stress, and Statins -- 1.6. Kruppel-Like Factor 4 (KLF4) -- 1.7. Future Directions -- Acknowledgements -- References -- Chapter 5 RHO FAMILY SMALL GTPASES IN SHEAR STRESS SIGNALING -- 1. Cytoskeletal Rearrangement in Response to Shear Stress -- 1.1. Role of RhoA in Shear-Induced Cytoskeletal Alignment -- 1.2. Role of Rac1 in Shear-Induced Cytoskeletal Alignment -- 1.3. Role of Cdc42 in Shear-Induced Cytoskeletal Alignment -- 1.3.1. Cdc42 Effects on the Microtubule Cytoskeleton -- 1.3.2. Cdc42 Effects on Intermediate Filaments -- 2. The Role of Rho GTPases in Endothelial Permeability and Intercellular Adhesion -- 2.1. Permeability -- 2.2. Intercellular Adhesion/Leukocyte Transmigration -- 3. Rho-, Rac- and Cdc42-Dependent Signaling Pathways Activated by Flow -- 3.1. Upstream Signaling Pathways for GTPase Regulation -- 3.1.1. Players Upstream of Rho Activity Regulation -- 3.1.2. Upstream Players in Rac Activation -- 3.1.3. Upstream Players in Cdc42 Activation -- 3.2. Downstream Signaling Activated by Rho GTPases -- 3.2.1. Rho Effectors and Gene Expression -- 3.2.2. Rac Effectors and Gene Expression -- 3.2.3. Cdc42 Effectors and Gene Expression -- 4. Rho GTPases in Development and in vivo -- 4.1. RhoA -- 4.2. Rac1 -- 4.3. Cdc42 -- 5. A Model for Rho GTPases in Mechanotransduction -- References -- Chapter 6 NITRIC OXIDE AND ENDOTHELIAL MITOCHONDRIAL FUNCTION: IMPLICATIONS FOR ISCHEMIA/REPERFUSION -- 1. The Mitochondrial ETC is a Source of ROS -- 2. NO is a Key Mitochondrial Regulator -- 3. Cultured EC Exposure to Shear Stress Affects Mitochondrial Function: Role of NO -- 4. Shear-Induced Mitochondrial ROS Initiate Intracellular Signaling -- 5. Cultured EC Exposure to H/RO Causes Mitochondrial and Cell Dysfunction -- 6. I/RP-Induced Mitochondrial Oxidative Stress Leads to Cardiomyocyte/Heart Injury.

7. Understanding the Mechanisms of EC Dysfunction in Cardiac I/RP -- Acknowledgments -- References -- Chapter 7 GENOMIC APPROACHES TO ENDOTHELIAL CELL PHENOTYPING -- 1. Introduction -- 2. Introduction to Microarray Technologies -- 3. Experimental Design and Data Analysis -- 3.1. Experimental Design -- 3.2. Data Analysis -- 3.2.1. Preprocessing -- 3.2.2. Differential Expression -- 3.2.3. Data Mining Strategies -- 4. Case Study -- 4.1. Introduction -- 4.2. Study Design and Methods -- 4.3. Results and Conclusions -- 4.4. Summary -- 5. Genomics Studies of Endothelium -- 5.1. Insights into Endothelial Heterogeneity -- 5.2. Hemodynamics and Atherosusceptibility -- 5.3. In vitro Genomics Approaches -- 5.4. In vivo Genomics Approaches -- 5.5. Comparison of In vitro vs. In vivo Approaches: -- 6. Summary -- Acknowledgments -- Web Resources -- References -- Chapter 8 ENDOTHELIAL CELL PROLIFERATION AND DIFFERENTIATION IN RESPONSETO SHEAR STRESS -- 1. Introduction -- 2. Effect of Shear Stress on EC Turnover and Survival -- 2.1. Disturbed Flow Increases EC Permeability -- 2.2. Disturbed Flow Promotes EC Proliferation and Apoptosis -- 2.3. Laminar Flow Increase EC Quiescence and Survival -- 3. Endothelium Repair -- 4. Effect of Shear Stress on EC Differentiation -- 5. Summary and Conclusion -- 6. Disclosure -- Acknowledgement -- References -- Chapter 9 VASCULAR DIFFERENTIATION OF STEM CELLS BY MECHANICAL FORCES -- 1. Stretch -- 2. Shear -- 3. Hydrostatic Pressure -- 4. Combined Forces -- 5. Summary -- References -- Chapter 10 TISSUE ENGINEERED BLOOD VESSELS: FROM THE BENCH TO THE BEDSIDE AND BACK AGAIN (DEVELOPMENT OF A VASCULAR CONDUIT FOR USE IN CONGENITAL HEART SURGERY) -- 1. Introduction -- 1.1. Pre-clinical Studies -- 1.2. Clinical Studies -- 1.3. Post-clinical Studies -- 2. Conclusion -- References.

Chapter 11 DESIGN IMPLICATIONS FOR ENDOVASCULAR STENTS AND THE ENDOTHELIUM -- 1. Stent Deployment and the Endothelium -- 1.1. Stent Struts Promote Disturbed Flow -- 1.2. Stent Deployment Compromises Endothelium -- 1.3. Stent Design Properties Affecting Restenosis -- 1.4. Drug Eluting Stents (DES) and the Endothelium -- 1.5. Elimination and Minimization of Disturbed Flow in the Vicinity of Stent Struts -- References -- Chapter 12 VASCULAR MIMETIC MICROFLUIDIC SYSTEMS FOR THE STUDY OF ENDOTHELIAL ACTIVATION AND LEUKOCYTE RECRUITMENT IN MODELS OF ATHEROGENESIS -- 1. Shear Stress Modulates Endothelial Adhesion Molecule Expression -- 2. Monocyte Recruitment During Atherosclerosis -- 3. Design and Fabrication of Vascular Mimetic Microfluidic Chambers -- 4. Adhesion Molecule Expression on Cultured Aortic Endothelium Studied in a Linear Gradient of Shear Stress -- 5. Monocyte Recruitment on Vascular Mimetics -- 6. Lipid Primes Endothelium for an Enhanced Response to Inflammation and Increases Monocyte Recruitment -- Summary -- Acknowledgement -- References -- Chapter 13 MICRO SHEAR STRESS SENSORS: FROM IN VITRO TO IN VIVO ASSESSMENT OF INFLAMMATORY RESPONSES -- 1. Overview and Clinical Relevance -- 1.1. MEMS Shear Stress Sensors to Assess Monocyte Recruitment -- 1.2. Operating Principle of MEMS Shear Stress Sensors -- 1.3. Unique Aspects of MEMS Shear Stress Sensor Fabrication -- 1.4. Interfacing MEMS Sensors with a Pulsatile Flow Channel -- 1.5. Nonlinear Displacement of Monocyte Locomotion in Response to Oscillatory Flow -- 1.6. Monocyte Binding to Bovine Aortic Endothelial Cells (BAEC) in Response to Pulsatile vs. Oscillatory Flow -- 2. Assess Low Reynolds Number Flow in the Arterial Bifurcations -- 2.1. A Novel Backside Wire Bonding for Biomedical Applications.

2.2. Integrating MEMS Sensors to Resolve Spatial Variations in Shear Stress in a 3-D Bifurcation Model.