Vascular Biology: Exercise Training and Vascular Disease

描述（由申请人提供）： 血管疾病（CVD）困扰着美国。疾病预防控制中心报告说，美国第二大死亡“实际原因”是不良饮食和缺乏运动。本PPG的主题是运动（EX）诱导的血管细胞表型改变是EX预防和治疗CVD的疗效的基础。我们的目标是：1）确定负责EX诱导的血管细胞表型变化的细胞/分子机制，2）应用 了解血管细胞生物学和EX诱导适应的机制，以了解EX对血管疾病的有益作用。和3）确定由EX产生的调节血管细胞表型的信号，以及多种信号如何相互作用，使得健康的血管细胞在面对不良饮食时得以保存。将使用高脂肪饲料（HFC）诱导的猪疾病模型。项目1检验了以下假设：EX通过增加L型电压门控Ca通道活性/表达以及通过阻止钙库操纵的Ca通道和中电导K通道的上调，赋予对HFC诱导的、致动脉粥样硬化的冠状动脉平滑肌（SM）表型调节的抵抗。项目3测试 EX恢复/保留正常冠状动脉内皮表型的假设。有人提出，内皮细胞基因，如一氧化氮合酶（eNOS）的表达改变，信号增加的剪切应力（Tw）在EX回合，在EX中发挥关键作用。项目5检验了EX通过脂蛋白脂酶（LPL）依赖性过程维持正常内皮表型的假设， 粘附分子和增强抗动脉粥样硬化基因如eNOS的表达。项目6检验了以下假设：Tw对于扩大至关重要，壁拉伸（Ts）对于保留股动脉闭塞后维持灌注的非常大的侧支动脉至关重要。在闭塞远端放置一个独特的动静脉分流器，可增加Tw和Ts。将在正常猪和HFC猪中检查Tw、Ts和EX的相互作用。程序项目作为一个整体完成了每个单独的项目 不能;这是一种多方面的方法，结合了最先进的分子、生物化学、细胞、药理学和生理学技术，用于猪、冠状动脉、单细胞和亚细胞成分，在血管生物学和运动科学中是独一无二的。我们独特的、多层次的研究EX诱导的血管适应性的方法和由PPG刺激的综合合作对于实现我们的研究至关重要。 陈述的目标。拟议的研究将促进对EXs维持血管健康的机制的理解，并将导致新的/改进的预防/治疗CVD的方法。

DESCRIPTION (provided by applicant): Vascular diseases (CVD) plague the US. The CDC reports the 2nd leading "actual cause" of death in the US is poor diet and physical inactivity. The theme of this PPG is that exercise (EX)-induced alterations in vascular cell phenotypes underlie the efficacy of EX in prevention and treatment of CVD. Our goals are: 1) Determine cellular/molecular mechanisms responsible for EX-induced changes in vascular cell phenotypes, 2) Apply knowledge of vascular cell biology and mechanisms of EX-induced adaptation to understanding the beneficial effects of EX on vascular disease., and 3) Determine the signals, generated by EX, that modulate vascular cell phenotype and how multiple signals interact so that healthy vascular cells are preserved in the face of poor diet. Porcine models of disease, induced with a high fat diet (HFC) will be used. Project 1 tests the hypothesis that EX confers resistance to HFC-induced, pro-atherogenic modulation of coronary smooth muscle (SM) phenotype by increasing L-type, voltage-gated Ca channel activity/expression and by preventing upregulation of store-operated Ca channels and intermediate-conductance K channels. Project 3 tests the hypothesis that EX restores/preserves normal coronary endothelial phenotype. It is proposed that altered expression of endothelial genes, such as nitric oxide synthase (eNOS), signaled by increased shear stress (Tw) during EX bouts, play key roles in EX. Project 5 tests the hypothesis that EX maintains normal endothelial phenotype through lipoprotein lipase (LPL)-dependent processes that blunt expression of proatherogenic adhesion molecules and enhance expression of anti-atherogenic genes such as eNOS. Project 6 tests the hypothesis that Tw is critical for enlargement and wall stretch (Ts) is critical for retention of very large collateral arteries sustaining perfusion following femoral artery occlusion. Tw and Ts will be increased with a unique A-V shunt placed distal to the occlusion. Interactive effects of Tw, Ts, and EX will be examined in normal and HFC pigs. The Program Project as a whole accomplishes what each individual project alone cannot; a multi-faceted approach incorporating state-of-the-art molecular, biochemical, cellular, pharmacologic, and physiologic techniques in pigs, coronary arteries, single cells and subcellular components that is unique in vascular biology and exercise science. Our unique, multi-level approach to study EX-induced vascular adaptation and the integrative collaboration stimulated by this PPG are crucial to accomplishing our stated goals. Proposed research will advance understanding of mechanisms whereby EXsustains vascular health and will lead to new/improved methods for prevention/treatment of CVD.