HYPERTENSION AND ARTERIAL INJURY--A ROLE FOR INTEGRINS

该项目的总体目标是验证高血压和动脉硬化可能通过一种涉及氧化应激的机制联系在一起的普遍假设。我们的工作假设是，高血压和动脉粥样硬化中的氧化应激诱导了特定整合素和细胞外基质（ECM）蛋白表达的类似改变，这些蛋白负责血管舒缩功能和血管平滑肌（VSM）表型的改变。我们最近的研究已经建立了VSM与内皮整合素和血管张力控制之间的新联系。此外，初步数据表明，氧化应激可以改变至少一种与血管舒缩活性相关的VSM整合素和一种作为该受体配体的ECM蛋白的表达。这些改变的整合素/基质相互作用可能使动脉壁易发生血管病变。该项目包括一个肾性高血压和动脉粥样硬化模型，将在大、中、微血管大小的动脉血管疾病发展的各个阶段进行研究。将评估氧化还原状态、整合素和ECM谱以及血管对可溶性和不可溶性整合素结合配体的反应性。这些配体将包括人工合成的含有精氨酸-甘氨酸-天冬氨酸（RGD）的多肽、I型胶原蛋白和骨桥蛋白，它们在血管损伤后会上调。我们的策略是结合完整血管、细胞、生化和分子方法的研究，为验证我们的假设和系统地整合我们的结果提供有力的方法。描述大、中、小动脉血管对已知整合素结合肽、I型胶原和骨桥蛋白在肾性高血压和/或施加氧化应激（烯丙胺处理）大鼠模型不同发育阶段的血管舒缩反应。血管活性将与氧化还原状态和整合素/ECM谱的测量相关。目的2：表征肾性高血压和动脉粥样硬化模型中导致氧化应激发展的血管氧化还原状态和机制，并评估NFkappaB作为常见信号转导途径的作用。目标3。表征和评估与肾性高血压或氧化应激相关的血管ECM/整合素表达在基因和蛋白质水平上的变化，并确定氧化应激对细胞外基质和整合素基因表达的影响。这些研究将为我们进一步了解高血压和动脉粥样硬化中的血管功能提供新的信息。

The overall goal of this project is to test the prevailing hypothesis that hypertension and arteriosclerosis may be linked through a mechanism that involves oxidative stress. Our working hypothesis is that oxidative stress in hypertension and atherosclerosis acts to induce similar alterations in the expression of specific integrins and extracellular matrix (ECM) proteins that are responsible for changes in vasomotor function and vascular smooth muscle (VSM) phenotype. Our recent studies have established a novel link between VSM and endothelial integrins and the control of vascular tone. In addition, preliminary data indicates that oxidative stress can alter the expression of at least one of the VSM integrins linked to vasomotor activity and an ECM protein that is a ligand for this receptor. These altered integrin/matrix interactions may predispose the arterial wall to development of vascular pathology. This project incorporates a model of renal hypertension and atherogenesis that will be studied at various stages of disease development in large, intermediate and microvascular sized arterial vessels. Assessments will be made of the redox status, integrin and ECM profiles and vascular reactivity to soluble and insoluble integrin-binding ligands. These ligands will include synthetic Arginine-Glycine-Aspartic Acid (RGD) containing peptides and type I collagen and osteopontin, which are up-regulated following vascular injury. Our strategy is combining studies of intact vessels, cellular, biochemical and molecular approaches will provide a powerful approach for testing our hypothesis and systematically integrating our results, The specific aims are: Aim 1: Characterize the vasomotor response for large intermediate and small arterial vessels to known integrin-binding peptides, type I collagen and osteopontin at varius stages of development for a rat model of renal hypertension and/or imposed oxidative stress (allylamine treated). Vasoactivity will be correlated with measurements of redox status and integrin/ECM profiles. Aim 2: Characterize the vascular redox status and mechanisms leading to the development of oxidative stress in models of renal hypertension and atherogenesis and evaluate the role of NFkappaB as a common signal transduction pathway. Aim 3. Characterize and evaluate changes in vascular ECM/integrin expression at the gene and protein levels that are associated with renal hypertension or oxidative stress and to define the influence of oxidative stress on extracellular matrix and integrin gene expression. These studies will provide new information that will advance our understanding vascular function in hypertension and atherosclerosis.