IGF I, its receptor and vascular remodeling

描述（由申请人提供）：高血压是西方世界最常见的疾病，是中风、肾衰竭和心肌梗死的主要原因。在高血压患者和动物模型中，小动脉平滑肌细胞层厚度增加是常见的。由于增厚的阻力血管壁可能作为血管放大器升高血压，调节微血管生长的因素可能有助于高血压的发展。血管紧张素II（angII）是一种多功能肽，在控制血压的生理过程和血管疾病的病理机制中起重要作用。有证据表明，血管紧张素II对血管系统的影响涉及其他生长因子。IGF I在细胞周期的S期起作用，它是细胞生长的关键调节剂，并且确实IGF I通过其受体（IGF IR）起作用，在调节血管平滑肌细胞（VSMC）增殖中具有中心作用。血管紧张素11增加大鼠肠系膜阻力动脉IGF-IR表达和平滑肌细胞复制。本项目的长期目标是确定IGF-IIIGF-IR系统在血管紧张素11诱导的VSMC生长在高血压触发的阻力动脉重塑中的作用。该提案的具体目标是：1.目的：1.证实血管紧张素II上调肠系膜动脉IGF-IR的非升压依赖性机制，并检测IGF-IR的上调是否与平滑肌细胞增殖有关.确定涉及Ras、RacI和NADPH氧化酶的信号通路是否产生激活SGK和NF-KB的活性氧，从而导致IGFJR转录增加和VSMC增殖。3.证明IGF JR表达增加导致p27下调，cdk 4和细胞周期蛋白DI上调以及细胞周期进展对angII.4的响应。证明血管中IGF IR的无效突变可抑制血管紧张素II诱导的VSMC增殖。我们的研究结果对开发调节高血压血管重塑的治疗方法具有重要的实际意义

DESCRIPTION (provided by the applicant): Hypertension is the most prevalent disease in the western world and is a major cause of stroke, renal failure and myocardial infarction. In patients as well as in animal models of hypertension an increased thickness of the smooth muscle cell layer of arterioles is common. Because thickened walls of resistance vessels may act as a vascular amplifier to raise blood pressure, factors that regulate the growth of micro-vessels may contribute to the development of hypertension. Angiotensin II (ang II) is a multifunctional peptide that plays a fundamental role in physiological processes controlling blood pressure and in pathological mechanisms underlying vascular disease. There is evidence, that ang II effects on the vasculature involve other growth factors. IGF I act at the S phase of the cell cycle, it is a critical regulator of cell growth and indeed IGF I acting via its receptor (IGF IR) has a central role in modulating vascular smooth muscle cell (VSMC) proliferation. Ang 11 infusion increases IGF IR expression and smooth muscle cell replication in rat mesenteric resistance arteries. The long-term goal of this project is to determine the role of IGF IIIGF IR system in ang 11-induced VSMC growth in hypertension triggered resistance artery remodeling. The specific aims of this proposal are:1. To document that ang II upregulates IGF IR in a pressor-independent mechanism in mesenteric arteries and to examine if upregulated IGF IR is associated with smooth muscle cell proliferation in vivo.2. To determine if a signaling pathway involving Ras, RacI and NADPH oxidase generates ROS that activate SGK and NF-KB leading to increased IGF JR transcription and VSMC proliferation.3. To demonstrate that increased expression of IGF JR leads to p27 down-regulation, up-regulation of cdk4 and cyclin DI and cell cycle progression in response to ang II.4. To demonstrate that ang II-induced proliferation of VSMC is blunted by a null mutation of the IGF IR in the vasculature.Our results should have important practical consequences for the development of therapies to modulate vascular remodeling in hypertension