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。美国疾病控制与预防中心报告称，美国第二大致死“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的变化是EX预防和治疗CVD的有效性的基础。我们的目标是：1)确定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对血管疾病的有益影响；以及3)确定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，从而在饮食不良的情况下保存健康的血管细胞。将使用高脂饮食(HFC)诱导的猪疾病模型。项目1验证了这样的假设，即EX通过增加L类型的电压门控性钙通道的活性/表达，并通过阻止钙通道和中电导K通道的上调来抵抗HFC诱导的冠状动脉平滑肌(SM)表型的促动脉粥样硬化调节。项目3测试 EX恢复/保留正常冠脉内皮细胞表型的假说。有研究认为，一氧化氮合酶(ENOS)等内皮基因表达的改变在EX中起着关键作用，这些基因是通过增加切应力(Tw)来传递信号的。项目5验证了这样的假设，即EX通过脂蛋白脂酶(LPL)依赖的过程钝化致动脉粥样硬化原的表达来维持正常的内皮表型 黏附分子，增强eNOS等抗动脉粥样硬化基因的表达。项目6验证了这样的假设，即Tw对于扩大至关重要，而壁拉伸(Ts)对于保留非常大的侧支动脉在股动脉闭塞后持续灌流是至关重要的。在咬合的远侧放置独特的房室分流装置，可增加TW和TS。Tw、Ts和ex的交互作用将在正常猪和HFC猪身上进行检验。计划项目作为一个整体完成了每个单独项目单独完成的任务 不能；这是一种多方面的方法，融合了猪、冠状动脉、单细胞和亚细胞成分的最先进的分子、生化、细胞、药理学和生理学技术，在血管生物学和运动科学中是独一无二的。我们独特的、多层次的方法来研究前诱导的血管适应，以及由这一PPG刺激的综合合作对于实现我们的 明确的目标。拟议的研究将促进对EXE维持血管健康的机制的理解，并将导致新的/改进的心血管疾病预防/治疗方法。

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.