Vascular Phenotypic Regulation by Growth Factors, Insulin and Glucose

生长因子、胰岛素和葡萄糖对血管表型的调节

• 批准号: 7986607
• 负责人: LAKSHMAN SEGAR
• 金额: $ 38.53万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986607
• 关键词: 1-Phosphatidylinositol 3-Kinase; 70-kDa Ribosomal Protein S6 Kinases; Acute; Angioplasty; Arterial Injury; Atherosclerosis; Attenuated; Blood Vessels; Chronic; Contractile Proteins; Development; Diabetes Mellitus; Disease; Down-Regulation; Event; Experimental Models; Fatty acid glycerol esters; Figs - dietary; GLUT4 gene; Gene Silencing; Glucose; Glucose Transporter; Glycolysis; Goals; Growth; Growth Factor; Human; Injury; Insulin; Insulin Receptor; Insulin Resistance; Intravenous; Knockout Mice; Metabolism; Modeling; Molecular; Mus; Phenotype; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Protein Isoforms; Protein Kinase; Receptor Signaling; Regulation; Role; Saphenous Vein; Serine; Serotonin; Serum Response Factor; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stenosis; Vasoconstrictor Agents; Vasospasm; Veins; Venous; cell growth; diabetic patient; feeding; glucose metabolism; glucose transport; glucose uptake; human FRAP1 protein; improved; inhibitor/antagonist; insight; insulin signaling; internal thoracic artery; non-diabetic; overexpression; prevent; public health relevance; restenosis; treatment strategy; vascular smooth muscle cell proliferation; vasoconstriction

DESCRIPTION (provided by applicant): The overall goal of this proposal is to gain new understanding into the mechanisms of atherosclerosis. The specific objective is to investigate how platelet-derived growth factor (PDGF) regulates glucose transport and insulin receptor signaling to influence phenotypic changes in vascular smooth muscle cells (VSMCs). The development of vascular complications in nondiabetic and diabetic patients correlates closely with increased VSMC glucose metabolism and dysregulated insulin signaling. Preliminary studies reveal that PDGF-induced VSMC proliferation is accompanied by enhanced glucose uptake through glucose transporters (GLUTs) and impaired insulin receptor signaling. Serine phosphorylation or downregulation of insulin receptor substrates (IRS-1/2) by PDGF attenuates insulin-induced IRS-associated phosphoinositide 3-kinase (PI 3-kinase) activity. We therefore hypothesize that PDGF contributes to vascular proliferative disease by altering glucose transport and insulin receptor signaling in VSMCs. Specific Aim 1 will determine the mechanism by which PDGF alters VSMC glucose transport and insulin signaling and its functional consequences in the glycolytic, proliferative, and contractile phenotype. This aim will use human aortic VSMCs to determine the differential effects of PDGF and insulin on glucose uptake, glycolysis, GLUT-1/GLUT-4 expression and translocation, IRS- 1/2 expression and phosphorylation, and the key signaling events/SRF transcription factor that regulate glycolytic, proliferative, and contractile phenotype. Constitutive overexpression and gene-silencing strategies will be employed to elucidate the distinct roles of GLUT isoforms and IRS isoforms in regulating VSMC phenotype. Specific Aim 2 will determine the mechanism by which systemic insulin resistance and/or GLUT4 deficiency alter injury-induced neointimal growth and PDGF- vs insulin-induced glucose transport. This aim will employ femoral arterial injury model in high-fat fed mice and GLUT4-null mice, to determine the roles of endogenous PDGF and glucose transporters toward neointimal growth, and the effects of intravenous PDGF vs insulin on neointimal glucose metabolism. Specific Aim 3 will determine the mechanism by which diabetes alters VSMC glucose transport and insulin signaling and its functional consequences in conduit vessel neointimal growth and vasoconstriction. This aim will utilize venous vs arterial grafts from nondiabetic and diabetic patients to determine how diabetes alters the chronic effects of PDGF (vs insulin) on VSMC glucose transport, IRS-1/2 signaling, and phenotypic changes. In addition, this aim will determine how diabetes alters the acute effects of vasoactive agonist, serotonin (vs insulin) on smooth muscle glucose uptake and contractility. Together, these studies will provide a better understanding of dysregulated glucose transport and metabolism that contribute to exaggerated VSMC growth and increased vasoreactivity in insulin-resistant states. The rationale for the proposed studies is that it will provide new insights into treatment strategies to ameliorate restenosis after angioplasty and stenotic complications in nondiabetic and diabetic patients. PUBLIC HEALTH RELEVANCE: Abnormal increases in glucose transport and metabolism in vascular smooth muscle cells (VSMCs) are implicated in the development of vascular proliferative diseases such as atherosclerosis, restenosis after angioplasty, vein graft stenosis, and vasospasm. The proposed studies investigate the detrimental effects of platelet-derived growth factor (PDGF) toward increased glucose uptake and impaired insulin receptor signaling in VSMCs. Strategies to inhibit PDGF receptor signaling may prevent dysregulated glucose metabolism and insulin signaling to improve vascular function in nondiabetic and diabetic patients.

描述（由申请人提供）：该提案的总体目标是获得对动脉粥样硬化机制的新认识。具体目标是研究血小板衍生生长因子 (PDGF) 如何调节葡萄糖转运和胰岛素受体信号传导，从而影响血管平滑肌细胞 (VSMC) 的表型变化。非糖尿病和糖尿病患者血管并发症的发生与 VSMC 葡萄糖代谢增加和胰岛素信号传导失调密切相关。初步研究表明，PDGF 诱导的 VSMC 增殖伴随着通过葡萄糖转运蛋白 (GLUT) 的葡萄糖摄取增强和胰岛素受体信号传导受损。 PDGF 的丝氨酸磷酸化或胰岛素受体底物 (IRS-1/2) 的下调会减弱胰岛素诱导的 IRS 相关磷酸肌醇 3-激酶 (PI 3-激酶) 活性。因此，我们假设 PDGF 通过改变 VSMC 中的葡萄糖转运和胰岛素受体信号传导而导致血管增殖性疾病。具体目标 1 将确定 PDGF 改变 VSMC 葡萄糖转运和胰岛素信号传导的机制及其在糖酵解、增殖和收缩表型中的功能后果。该目标将使用人主动脉 VSMC 来确定 PDGF 和胰岛素对葡萄糖摄取、糖酵解、GLUT-1/GLUT-4 表达和易位、IRS-1/2 表达和磷酸化以及关键信号转导事件/SRF 转录的差异影响调节糖酵解、增殖和收缩表型的因子。将采用组成型过表达和基因沉默策略来阐明 GLUT 亚型和 IRS 亚型在调节 VSMC 表型中的不同作用。具体目标 2 将确定全身胰岛素抵抗和/或 GLUT4 缺乏改变损伤诱导的内膜生长和 PDGF 与胰岛素诱导的葡萄糖转运的机制。该目标将采用高脂喂养小鼠和 GLUT4-null 小鼠的股动脉损伤模型，以确定内源性 PDGF 和葡萄糖转运蛋白对新内膜生长的作用，以及静脉注射 PDGF 与胰岛素对新内膜葡萄糖代谢的影响。具体目标 3 将确定糖尿病改变 VSMC 葡萄糖转运和胰岛素信号传导的机制及其在导管血管新生内膜生长和血管收缩中的功能后果。该目标将利用来自非糖尿病和糖尿病患者的静脉与动脉移植物来确定糖尿病如何改变 PDGF（与胰岛素）对 VSMC 葡萄糖转运、IRS-1/2 信号传导和表型变化的慢性影响。此外，这一目标将确定糖尿病如何改变血管活性激动剂、血清素（相对于胰岛素）对平滑肌葡萄糖摄取和收缩力的急性影响。总之，这些研究将有助于更好地理解葡萄糖转运和代谢失调，这些失调导致 VSMC 过度生长和胰岛素抵抗状态下血管反应性增加。拟议研究的理由是，它将为改善非糖尿病和糖尿病患者血管成形术后再狭窄和狭窄并发症的治疗策略提供新的见解。 公众健康相关性：血管平滑肌细胞 (VSMC) 中葡萄糖转运和代谢的异常增加与动脉粥样硬化、血管成形术后再狭窄、静脉移植物狭窄和血管痉挛等血管增殖性疾病的发生有关。拟议的研究调查了血小板衍生生长因子 (PDGF) 对 VSMC 中葡萄糖摄取增加和胰岛素受体信号传导受损的不利影响。抑制 PDGF 受体信号传导的策略可以防止葡萄糖代谢和胰岛素信号传导失调，从而改善非糖尿病和糖尿病患者的血管功能。