IGF I, its receptor and vascular remodeling

描述（由申请人提供）：高血压是西方世界最普遍的疾病，是中风、肾衰竭和心肌梗塞的主要原因。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充当血管放大器而升高血压，因此调节微血管生长的因素可能会导致高血压的发生。血管紧张素 II (ang II) 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发挥着重要作用。有证据表明血管紧张素II对脉管系统的影响涉及其他生长因子。 IGF I 在细胞周期的 S 期发挥作用，是细胞生长的关键调节因子，实际上 IGF I 通过其受体 (IGF IR) 发挥作用，在调节血管平滑肌细胞 (VSMC) 增殖中发挥核心作用。 Ang 11 输注可增加大鼠肠系膜阻力动脉中 IGF IR 的表达和平滑肌细胞的复制。该项目的长期目标是确定 IGF IIIGF IR 系统在高血压引发的阻力动脉重塑中 ang 11 诱导的 VSMC 生长中的作用。本提案的具体目标是： 1．证明ang II在肠系膜动脉中以升压独立的机制上调IGF IR，并检查上调的IGF IR是否与体内平滑肌细胞增殖相关。2．确定涉及 Ras、RacI 和 NADPH 氧化酶的信号通路是否会产生 ROS，从而激活 SGK 和 NF-KB，从而导致 IGF JR 转录和 VSMC 增殖增加。3．证明 IGF JR 表达增加导致 p27 下调、cdk4 和细胞周期蛋白 DI 上调以及响应 ang II.4 的细胞周期进程。证明 Ang II 诱导的 VSMC 增殖被血管系统中 IGF IR 的无效突变所削弱。我们的结果对于开发调节高血压血管重塑的疗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