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: 9336435
• 负责人: PAMELA C LOVERN
• 金额: $ 36.17万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336435
• 关键词: Advanced Glycosylation End Products; Affect; Age; American; Amputation; Arteries; Award; Binding Proteins; Blood Vessels; Blood flow; Bypass; Cardiovascular Diseases; Clinical; Coculture Techniques; Cone; Consumption; Cultured Cells; Data; Devices; Endothelial Cells; Exhibits; Ferritin; Functional disorder; Genetic Transcription; Growth; Hindlimb; Hyperglycemia; In Vitro; Iron; Iron-Regulatory Proteins; Ischemia; Knowledge; Learning; Left; Limb structure; Link; Liquid substance; Lower Extremity; Metabolic; Modeling; Molecular; Mus; New Territories; Non-Insulin-Dependent Diabetes Mellitus; PGF gene; Pathway interactions; Patients; Peripheral; Peripheral arterial disease; Placental Growth Factor; Process; Procollagen-Proline Dioxygenase; Proteins; Publishing; Reactive Oxygen Species; Recovery; Regulation; Regulatory Pathway; Response Elements; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Smooth Muscle Myocytes; Stress; Study models; System; TNF gene; Testing; Therapeutic Intervention; Trauma; Up-Regulation; arteriole; artery occlusion; diabetic; feeding; femoral artery; hemodynamics; high risk; improved; in vivo; insight; intervention effect; iron metabolism; limb amputation; novel; prevent; shear stress; western diet

PROJECT SUMMARY Type II diabetics are at very high risk for cardiovascular diseases, and ~30% of diabetics over age 50 suffer from peripheral artery disease (PAD). PAD affects ~10 million Americans and has a devastating clinical impact; current treatments often fail to provide long-term benefits, and amputation is the final option for patients with critical limb ischemia. More than 90% of non-trauma related limb amputations in the US are due to PAD. Arteriogenesis, the ability of the vasculature to bypass occlusion via enlargement of pre-existing collateral arteries, could improve blood flow in PAD patients; unfortunately, type II diabetes inhibits arteriogenesis. Since stimulation of arteriogenesis would be of enormous value in diabetics with PAD, it is essential that we comprehend 1) key mechanisms of arteriogenesis and 2) how these are blocked by type II diabetes. Placental growth factor (PLGF) specifically induces arteriogenesis and is a key initiating factor in the process. However, little is known about how PLGF levels are controlled. We made several key discoveries under the prior award that revealed a novel mechanism linking upregulation of PLGF to the arteriogenic signal of fluid shear stress (FSS). Furthermore, we established that a Western diet inhibits occlusion-induced PLGF expression in skeletal muscle, and gained insights into the mechanism involved. The overall objectives of this application are 1) to further pursue our knowledge of mechanisms regulating PLGF, and 2) to reveal the mechanism by which a Western diet impairs PLGF regulation. Our central hypotheses are: 1) FSS upregulates PLGF via a novel iron-dependent pathway; and 2) a Western diet inhibits PLGF expression by inducing sustained hyperglycemia. These hypotheses are strongly supported by our published results and preliminary data. We will accomplish three Specific Aims. Specific Aim 1 will expand our understanding of the molecular mechanism for upregulation of PLGF by fluid shear stress in vitro. These studies utilize an endothelial cell/smooth muscle cell co-culture model; pulsatile FSS is applied with a cone and plate device. This model was established in our lab under the prior award. Specific Aim 2 will extend our knowledge of the molecular mechanism for upregulation of PLGF by FSS from in vitro to ex vivo and in vivo systems. Models for these studies are isolated mouse peripheral arterioles and gradual femoral artery occlusion in mice; both are established in our lab. Specific Aim 3 will discover molecular mechanism(s) by which a Western diet causes dysfunctional PLGF regulation. These studies are done in cultured cells, and in isolated peripheral arterioles and ischemic hindlimbs of mice exhibiting a range of metabolic dysfunction induced by long-term Western diet consumption. These studies will reveal novel mechanisms regulating expression of this key arteriogenic growth factor and will identify new targets for potential therapeutic interventions to enhance arteriogenesis in diabetic PAD.

项目概要 II 型糖尿病患者患心血管疾病的风险非常高，约 30% 的 50 岁以上糖尿病患者患有心血管疾病 外周动脉疾病（PAD）。 PAD 影响约 1000 万美国人，并具有毁灭性的临床影响； 目前的治疗方法往往无法提供长期益处，截肢是患者的最终选择 肢体严重缺血。在美国，超过 90% 的非外伤相关肢体截肢都是由外周动脉疾病 (PAD) 造成的。 动脉生成，脉管系统通过扩大预先存在的侧支循环来绕过闭塞的能力 动脉，可以改善 PAD 患者的血流；不幸的是，II 型糖尿病会抑制动脉生成。自从 刺激动脉生成对于患有 PAD 的糖尿病患者具有巨大的价值，因此我们必须 了解 1) 动脉生成的关键机制以及 2) II 型糖尿病如何阻断这些机制。胎盘素 生长因子（PLGF）特异性诱导动脉生成，是该过程中的关键启动因子。然而， 关于如何控制 PLGF 水平知之甚少。我们在之前的奖项中取得了几项关键发现 揭示了一种将 PLGF 上调与流体剪切应力的动脉信号联系起来的新机制 （金融服务局）。此外，我们确定西方饮食会抑制骨骼中闭塞诱导的 PLGF 表达。 肌肉，并深入了解所涉及的机制。该应用程序的总体目标是 1) 进一步探究我们对 PLGF 调节机制的了解，以及 2）揭示 西方饮食会损害 PLGF 调节。我们的中心假设是：1) FSS 通过一种新颖的方法上调 PLGF 铁依赖性途径； 2) 西方饮食通过诱导持续的 PLGF 表达来抑制 PLGF 表达。 高血糖。这些假设得到了我们公布的结果和初步数据的有力支持。我们 将实现三个具体目标。具体目标 1 将扩展我们对分子的理解 体外流体剪切应力上调 PLGF 的机制。这些研究利用内皮细胞 细胞/平滑肌细胞共培养模型；脉冲 FSS 采用锥板装置。这个型号 是根据先前的奖项在我们的实验室建立的。具体目标 2 将扩展我们对分子的了解 FSS 从体外到离体和体内系统上调 PLGF 的机制。这些的模型 研究是分离小鼠外周小动脉和小鼠股动脉逐渐闭塞；两者都是 在我们的实验室建立。具体目标 3 将发现西方饮食导致的分子机制 PLGF 调节功能失调。这些研究是在培养细胞和分离的外周小动脉中进行的 长期西方饮食引起的一系列代谢功能障碍的小鼠后肢缺血 消耗。这些研究将揭示调节这一关键动脉生长表达的新机制 因素，并将确定潜在治疗干预的新目标，以增强糖尿病患者的动脉生成 软垫。