IGF I, its receptor and vascular remodeling

IGF I、其受体与血管重塑

• 批准号: 6508322
• 负责人: JIE DU
• 金额: $ 3.75万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2002-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6508322
• 关键词: angiogenesis; angiotensin II; biological signal transduction; cell cycle; cell growth regulation; cell proliferation; cyclins; growth factor receptors; hypertension; insulinlike growth factor; laboratory rat; mesenteric artery; nuclear factor kappa beta; oxidative stress; receptor expression; vascular resistance; vascular smooth muscle

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

描述(申请人提供)：高血压是西方世界最流行的疾病，也是中风、肾功能衰竭和心肌梗死的主要原因。在高血压患者和动物模型中，小动脉的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起到血管放大器的作用，从而提高血压，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(Ang II)是一种多功能多肽，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，Ang II对血管系统的影响涉及其他生长因子。胰岛素样生长因子I作用于细胞周期的S期，是细胞生长的重要调节因子，而通过其受体(IGFIR)作用的胰岛素样生长因子I在调节血管平滑肌细胞的增殖中起着核心作用。血管紧张素转换酶11可增加大鼠肠系膜阻力动脉IGF-IR的表达和平滑肌细胞的复制。本项目的长期目标是确定IGF-IIIGF-IR系统在血管紧张素转换酶11(Ang-11)诱导的VSMC在高血压触发的阻力动脉重构中的作用。本研究的具体目的是：1.研究血管紧张素转换酶II上调肠系膜动脉胰岛素样生长因子IR的升压作用，并研究IGF IR上调是否与活体血管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ROS，从而激活SGK和NF-KB，导致IGF Jr转录增加和VSMC增殖。为了证明IGF Jr的表达增加导致p27下调，CDK4和Cyclin DI上调，以及Ang II反应的细胞周期进展。为了证明血管紧张素转换酶II诱导的血管平滑肌细胞的增殖被血管中胰岛素样生长因子受体零突变所钝化，我们的结果将对高血压血管重塑调节治疗的发展具有重要的实际意义