Mechanisms of neovascularization in response to ischemia

缺血反应的新生血管形成机制

• 批准号: 9086396
• 负责人: Victoria L Bautch
• 金额: $ 37.57万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086396
• 关键词: Adaptor Signaling Protein; Architecture; Arteriosclerosis; Binding; Blood typing procedure; Cardiovascular Diseases; Cardiovascular Physiology; Cell Proliferation; Cell physiology; Cells; Cholesterol; Collagen; Complex; Coupled; Data; Development; Disease; Endothelial Cells; Environment; Fluorescence; Fluorescence Resonance Energy Transfer; Glean; Growth; Health; Hindlimb; Image Analysis; In Vitro; Inflammation; Integrins; Ischemia; KDR gene; Lead; Ligation; Liquid substance; Mechanics; Mediating; Modeling; Molecular; Mus; Patients; Perfusion; Peripheral Vascular Diseases; Positioning Attribute; Process; Protein Deficiency; Proteins; Proteomics; Publishing; Recovery; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Structure; Testing; Therapeutic; Tissues; Transgenic Mice; Trees; Tyrosine Phosphorylation; Vascular remodeling; Work; Wound Healing; angiogenesis; base; blood group; blood perfusion; clinically relevant; femoral artery; gene therapy; hemodynamics; hypercholesterolemia; improved; in vitro Model; in vivo; insight; mutant; neovascularization; novel; oxidized low density lipoprotein; postnatal; protein activation; receptor; repaired; research study; response; restoration; shear stress; small molecule; therapeutic development

DESCRIPTION (provided by applicant): Neovascularization in response to ischemia is an important repair process, which is severely compromised in the setting of chronically elevated cholesterol. Therapeutic neovascularization trials have revealed dramatically reduced responses in hypercholesterolemic patients; however, there is little information on the effects of hypercholesterolemia on arteriogenesis. Arteriogenesis, the outward remodeling of collateral vessels that form bridges between arterial networks, is critical for recovery of blood perfusion to the ischemic tissue after occlusion. Collateral remodeling is driven by a sudden increase in hemodynamic forces, especially shear stress, resulting from the drastic increase in flow through collaterals. This increase in shear stress is sensed by mechanosensory proteins expressed in endothelial cells (ECs), which initiate signal transduction pathways that induce processes such as cell proliferation and inflammation. Despite significant efforts to increase collateral growth and perfusion recovery in the setting of ischemia using small molecules and gene therapy approaches, results have been largely disappointing, underscoring the importance of studies on understanding the molecular mechanisms that drive arteriogenesis. Recently published work from our group, coupled with nascent observations provided in this application, identify the signaling protein adaptor protein Src homologous and collagen protein (Shc) as an essential regulator of neovascularization. To better understand the role of Shc in neovascularization, three interrelated aims are proposed. Aim 1 will determine the role of Shc in neovascularization in response to ischemia in the setting of hypercholesterolemia. Aim 2 will determine the role of Shc in endothelial mechanotransduction under defined collateral hemodynamic conditions in vitro. Aim 3 will determine the molecular determinants in Shc that facilitate neovascularization. Experiments proposed in this proposal will contribute to our understanding of molecular mechanisms of arteriogenesis and collateral remodeling. Elucidation of some of the signals that regulate post-ischemic neovascularization is needed in order to develop therapeutic strategies for diseases such as peripheral vascular disease, arteriosclerosis and wound healing.

描述（由申请人提供）：缺血后的新生血管形成是一个重要的修复过程，在胆固醇长期升高的情况下，这一过程受到严重损害。治疗性新生血管试验显示，高胆固醇血症患者的反应显著降低；然而，关于高胆固醇血症对动脉形成的影响的信息很少。动脉生成，即在动脉网络之间形成桥梁的侧支血管的向外重塑，对于血液灌注恢复至关重要