HYPERTENSION AND ARTERIAL INJURY--A ROLE FOR INTEGRINS

这个项目的总体目标是测试流行的假设，即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。我们的工作假设是，高血压和动脉粥样硬化中的氧化应激导致特定整合素和细胞外基质(ECM)蛋白的表达发生类似的变化，这些蛋白导致血管运动功能和血管平滑肌(VSM)表型的变化。我们最近的研究已经建立了VSM和内皮整合素以及血管张力控制之间的新的联系。此外，初步数据表明，氧化应激可以改变至少一个与血管运动活性相关的VSM整合素的表达，以及作为该受体配体的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于发生血管病变。该项目结合了肾性高血压和动脉粥样硬化的模型，该模型将在疾病发展的不同阶段在大、中和微血管大小的动脉血管中进行研究。将对氧化还原状态、整合素和ECM图谱以及对可溶性和不溶性整合素结合配体的血管反应性进行评估。这些配体将包括合成的含有精氨酸-甘氨酸-天冬氨酸(RGD)的多肽以及I型胶原和骨桥蛋白，它们在血管损伤后表达上调。我们的策略是结合对完整血管的研究，细胞、生化和分子方法将为检验我们的假设和系统地整合我们的结果提供一个强有力的方法，具体目标是：目标1：在肾性高血压和/或强制氧化应激(烯丙胺治疗)的大鼠模型中，表征大、中、小动脉对已知的整合素结合肽、I型胶原和骨桥蛋白在不同发育阶段的血管运动反应。血管活性将与氧化还原状态和整合素/ECM曲线的测量相关联。目的：研究肾性高血压和动脉粥样硬化模型中血管氧化还原状态及其导致氧化应激的机制，探讨NFkappaB作为共同信号转导途径的作用。目的3.从基因和蛋白水平研究与肾性高血压或氧化应激相关的血管ECM/整合素表达的变化，明确氧化应激对细胞外基质和整合素基因表达的影响。这些研究将提供新的信息，促进我们对高血压和动脉粥样硬化中血管功能的了解。

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.