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: 8116966
• 负责人: LAKSHMAN SEGAR
• 金额: $ 8.61万
• 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 2011-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116966
• 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; 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对动脉粥样硬化的机制有了新的了解。具体目标是研究血小板衍生的生长因子（PDGF）如何调节葡萄糖转运和胰岛素受体信号传导以影响血管平滑肌细胞（VSMC）的表型变化。非糖尿病患者和糖尿病患者血管并发症的发展与VSMC葡萄糖代谢增加和胰岛素信号失调密切相关。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）和受损的胰岛素受体信号传导增强的葡萄糖摄取。 PDGF通过PDGF减弱胰岛素诱导的IRS相关磷酸肌醇3-激酶（PI 3-激酶）活性的胰岛素受体底物（IRS-1/2）的丝氨酸磷酸化或下调。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来促进血管增殖性疾病。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及其在糖酵解，增殖和收缩表型中的功能后果的机制。该目标将使用人体主动脉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事件/SRF转录因子的差异影响。将采用组成型过表达和基因沉默策略来阐明GLUT同工型和IRS同工型在调节VSMC表型中的不同作用。具体的目标2将确定全身性胰岛素抵抗和/或GLUT4缺乏症会改变损伤引起的新内膜生长以及PDGF-与胰岛素诱导的葡萄糖转运的机制。该目标将在高脂喂养的小鼠和GLUT4-NULL小鼠中采用股动脉损伤模型，以确定内源性PDGF和葡萄糖转运蛋白对新内膜生长的作用，以及静脉内PDGF与胰岛素对新内膜葡萄糖代谢的影响。特定的目标3将确定糖尿病通过在导管血管新内膜生长和血管收缩中改变VSMC葡萄糖传输和胰岛素信号传导的机制。该目标将利用非糖尿病患者和糖尿病患者的静脉移植物来确定糖尿病如何改变PDGF（VS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，此目标将决定糖尿病如何改变血管活性激动剂，5-羟色胺（VS胰岛素）对平滑肌葡萄糖摄取和收缩力的急性影响。总之，这些研究将更好地理解失调的葡萄糖转运和代谢，这有助于夸大VSMC生长并增加抗胰岛素耐药性状态的血管反应性。拟议的研究的基本原理是，它将为非糖尿病患者和糖尿病患者的血管成形术和狭窄并发症后改善再狭窄的治疗策略提供新的见解。 公共卫生相关性：血管平滑肌细胞（VSMC）中葡萄糖转运和代谢异常的增加与血管增殖性疾病的发展有关，例如动脉粥样硬化，血管成形术后血管造成病后的再狭窄，静脉移植狭窄和血管痉挛。拟议的研究研究了血小板衍生的生长因子（PDGF）对VSMC中葡萄糖摄取增加和胰岛素受体信号受损的有害作用。抑制PDGF受体信号传导的策略可能会阻止葡萄糖代谢失调和胰岛素信号传导，以改善非糖尿病和糖尿病患者的血管功能。