Regulation of placenta growth factor by hemodynamics and reactive oxygen species

血流动力学和活性氧对胎盘生长因子的调节

• 批准号: 7894652
• 负责人: PAMELA C LOVERN
• 金额: $ 35.77万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894652
• 关键词: Accounting; Affect; American; Animal Model; Animals; Arteries; Biological; Biological Models; Blood Vessels; Blood flow; Bypass; Cardiovascular Diseases; Cardiovascular system; Cell Culture System; Cell Culture Techniques; Cells; Clinical; Clinical Research; Coculture Techniques; Combined Modality Therapy; Complex; Complications of Diabetes Mellitus; Coronary; Coronary Arteriosclerosis; Data; Defect; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Distal; Dose; Endothelial Cells; Epoprostenol; Experimental Models; Face; Fatty acid glycerol esters; Functional disorder; Future; Generations; Goals; Growth; Growth Factor; Hydrogen Peroxide; Hyperglycemia; Hyperlipidemia; In Vitro; Knowledge; Link; Literature; Measurement; Measures; Mediator of activation protein; Messenger RNA; Metabolic; Metabolic syndrome; Molecular; Molecular and Cellular Biology; Mus; Nitric Oxide; Outcome; Oxidative Stress; Patients; Peripheral arterial disease; Physiological; Physiological Processes; Placental Growth Factor; Positioning Attribute; Production; Proteins; Reactive Oxygen Species; Regulation; Research; Risk; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Streptozocin; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Work; artery occlusion; base; design; diabetic; diabetic cardiomyopathy; diabetic patient; functional improvement; hemodynamics; improved; in vivo; in vivo Model; innovation; mortality; mouse model; mutant mouse model; novel; public health relevance; research study; response; shear stress

DESCRIPTION (provided by applicant): Collateral artery enlargement (arteriogenesis) is a physiological process that can 'bypass' atherosclerotic supply arteries to preserve blood flow to distal tissue. Thus, pharmacological stimulation of arteriogenesis could be highly beneficial in the treatment of ischemic vascular diseases, such as coronary artery disease (CAD) and peripheral artery disease (PAD). Such treatments would be especially valuable in the setting of diabetes, which both 1) severely increases the risk of CAD and PAD and 2) inhibits native (unstimulated) arteriogenesis. Placenta growth factor (PlGF, PGF) is a VEGF-related growth factor that specifically favors the expansion of arteries via arteriogenesis. Thus, therapeutic stimulation of PlGF expression could potentially be used to enhance arteriogenesis and improve clinical outcomes in patients with CAD and PAD. However, such treatments are not currently possible, due to a lack of understanding of the basic mechanism(s) regulating PlGF expression. Our preliminary data suggests the existence of a novel mechanism regulating PlGF expression in the vascular wall. Moreover, our evidence suggests that this mechanism is dysfunctional in diabetes. Thus, dysregulation of PlGF expression may contribute to faulty arteriogenesis in diabetics. The LONG TERM GOAL of this research is to elucidate key mechanisms regulating PlGF expression under physio- and patho-physiological conditions. This project will pursue three Specific Aims. Specific Aim 1: Establish the basic regulatory mechanism controlling PlGF expression in the vascular wall. These studies will be performed in three complementary model systems: primary vascular smooth muscle cells (SMC) in static culture; co- cultured vascular endothelial cells (EC) and SMC which are exposed to shear stress; and isolated perfused mouse vessels. Specific Aim 2: Identify key steps in the basic PlGF regulatory mechanism that are altered by diabetes. These studies will confirm the physiological relevance of the mechanism(s) uncovered in Aim 1. These experiments will be conducted in mouse models of hyperglycemia (streptozotocin treatment), hyperlipidemia (high-fat diet treatment) and combined hyperglycemia/hyperlipidemia. This design will allow us 1) to determine what facet of the complex metabolic dysfunction that typically occurs in diabetes inhibits PlGF expression, and 2) to pinpoint the regulatory step at which inhibition of PlGF expression occurs. Specific Aim 3: Assess the ability of enhanced endogenous PlGF expression to stimulate arteriogenesis. These studies will take the results of Aim 2 to the next level by determining whether correction of the signaling defect revealed in Aim 2 can 1) reverse the inhibition of PlGF expression in diabetes, and 2) result in functional improvement as measured by capacity to undergo arteriogenesis in response to vascular occlusion. These innovative and novel studies will provide essential new information about the regulation of an important arteriogenic factor and will provide "proof of concept" for the idea that normalizing or enhancing PlGF expression can improve the arteriogenic response to vascular occlusion (due to CAD or PAD) in patients with diabetes. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Ischemic cardiovascular diseases (CVD) such as coronary artery disease are highly prevalent in diabetics and account for most of the mortality in this patient group. Stimulation of collateral artery growth (arteriogenesis) to create a physiological "bypass" is a promising treatment concept; however, greater understanding of the mechanisms controlling arteriogenesis is needed before such treatments are a reality. This research will investigate fundamental mechanisms regulating the key arteriogenic growth factor PlGF as a basis for developing new, noninvasive treatments for ischemic CVD.

描述（由申请人提供）： 侧支动脉扩张（动脉生成）是一种生理过程，可以“绕过”动脉粥样硬化的供应动脉，以保留流向远端组织的血流。因此，药物刺激动脉生成对于治疗缺血性血管疾病（例如冠状动脉疾病（CAD）和外周动脉疾病（PAD））非常有益。此类治疗对于糖尿病患者尤其有价值，因为糖尿病会 1) 严重增加 CAD 和 PAD 的风险，2) 抑制天然（未刺激的）动脉生成。胎盘生长因子（PlGF、PGF）是一种 VEGF 相关生长因子，特别有利于通过动脉生成扩张动脉。因此，PlGF 表达的治疗刺激可能可用于增强 CAD 和 PAD 患者的动脉生成并改善临床结果。然而，由于缺乏对调节 PlGF 表达的基本机制的了解，目前尚不可能进行此类治疗。我们的初步数据表明，血管壁中存在调节 PlGF 表达的新机制。此外，我们的证据表明这种机制在糖尿病中是功能失调的。因此，PlGF 表达失调可能导致糖尿病患者动脉生成缺陷。本研究的长期目标是阐明在生理和病理生理条件下调节 PlGF 表达的关键机制。该项目将追求三个具体目标。具体目标1：建立控制血管壁中PlGF表达的基本调控机制。这些研究将在三个互补的模型系统中进行：静态培养的原代血管平滑肌细胞（SMC）；共培养的血管内皮细胞（EC）和SMC暴露于剪切应力；和分离的灌注小鼠血管。具体目标 2：确定基本 PlGF 调节机制中因糖尿病而改变的关键步骤。这些研究将证实目标 1 中发现的机制的生理相关性。这些实验将在高血糖（链脲佐菌素治疗）、高脂血症（高脂肪饮食治疗）和组合高血糖/高脂血症的小鼠模型中进行。这种设计将使我们能够 1) 确定糖尿病中通常发生的复杂代谢功能障碍的哪个方面抑制 PlGF 表达，2) 查明发生 PlGF 表达抑制的调节步骤。具体目标 3：评估增强的内源性 PlGF 表达刺激动脉生成的能力。这些研究将通过确定纠正目标 2 中揭示的信号缺陷是否可以 1) 逆转糖尿病中 PlGF 表达的抑制，以及 2) 导致功能改善（通过承受能力来衡量），将目标 2 的结果提升到一个新的水平。响应血管闭塞的动脉生成。这些创新和新颖的研究将提供有关重要动脉生成因子调节的重要新信息，并将为以下观点提供“概念证明”：正常化或增强 PlGF 表达可以改善对血管闭塞（由于 CAD 或 PAD）的动脉生成反应。糖尿病患者。 公共卫生相关性：项目叙述 冠状动脉疾病等缺血性心血管疾病 (CVD) 在糖尿病患者中非常普遍，是该患者群体死亡的主要原因。刺激侧支动脉生长（动脉生成）以创建生理“旁路”是一个有前途的治疗概念；然而，在这种治疗成为现实之前，需要更好地了解控制动脉生成的机制。这项研究将研究调节关键动脉生长因子 PlGF 的基本机制，作为开发新的、无创的缺血性 CVD 治疗方法的基础。