IGF I, its receptor and vascular remodeling

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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