VASCULAR BIOLOGY: EXERCISE TRAINING AND CORONARY DISEASE

该PPG的中心主题是，运动训练（EX）通过有益地改变冠状动脉平滑肌（CSM）和内皮细胞的功能和表型，有利于治疗冠心病（CHD）并减缓其发展。我们有三大目标：1）阐明调节CSM和内皮的细胞/分子机制; 2）确定EX诱导的血管阻力和渗透性控制变化的机制;和3）将血管生物学和适应机制的理解应用于CHD（饮食诱导的高脂血症）模型。我们的工作揭示了在组织和细胞/分子水平上EX诱导的冠状动脉功能改变的重要特征。我们将通过一种综合的实验方法来检验关于这些适应性机制的假设，该方法检查了整个冠状动脉树的功能。第一个项目测试的假设，即EX增加CSM L型VGCC的数量和/或活性，并且增加的张力是由EX-CSM中的Ca内流和K电流的相互作用引起的。项目2检验了以下假设：EX通过K通道的代谢和受体调节改变腺苷（ADO）和内皮素-1（ET-1）的CSM受体信号传导机制，并改变CSM ADO转运蛋白，从而改变腺苷（ADO）和内皮素-1（ET-1）的ADO机制，并改变CSM ADO转运蛋白，从而改变ADO敏感性。项目3检验了EX增加编码内皮源性介质和血管抗氧化系统的基因表达以及动脉大小、位置和机械力影响EX对内皮表型的影响的假设。项目4检验了NO依赖性机制是EX后ADO诱导的渗透性和交换增加的基础的假设，并将检验关于冠状动脉微血管中形成交换屏障的结构和所涉及的信号传导机制的假设。我们将继续与研究人员密切合作，实现我们的目标。我们在猪、冠状血管、单细胞和亚细胞成分中采用了分子、生物化学、细胞、药理学和生理学技术的多方面方法，这在运动科学中是独一无二的。这项研究将促进对冠状动脉适应的细胞/分子机制的理解，并可能揭示预防和治疗CHD的新方法和/或改进方法。

The central theme of this PPG is that exercise training (EX) is beneficial in treating of and blunts development of coronary heart disease (CHD) by beneficial alterations in function and phenotype of coronary smooth muscle (CSM) and endothelial cells. We have 3 major goals: 1) Elucidate cellular/molecular mechanisms regulating CSM and endothelium; 2) Determine mechanisms of EX-induced changes in control of vascular resistance and permeability; and 3) Apply understanding of vascular biology and mechanisms of adaptation to models of CHD (diet induced hyperlipidemia). Our work reveals important features of EX-induced alterations in coronary function at tissue and cellular/molecular levels. We will test hypotheses concerning these adaptive mechanisms with an integrated experimental approach examining function throughout the coronary tree. The first project tests the hypothesis that EX increases the number and/or activity of CSM L-type VGCCs, and that increased tone is caused by interactions of Ca influx and K currents in EX-CSM. Project 2 tests the hypothesis that EX alters CSM receptor signaling mechanisms of adenosine (ADO) and endothelin-1 (ET-1) and alters CSM ADO transporters and thereby ADO mechanisms of adenosine (ADO) and endothelin-1 (ET-1) and alters CSM ADO transporters and thereby ADO sensitivity via metabolism and receptor regulation of K channels. Project 3 tests the hypothesis that EX increases expression of genes coding for endothelium-derived mediators and vascular antioxidant systems and that artery size, location, and mechanical forces influences the effects of EX on endothelial phenotype. Project 4 tests the hypothesis that NO- dependent mechanisms underlie ADO-induced increases in permeability and exchange following EX and will test hypotheses concerning structures forming exchange barrier in coronary microvessels, and the signaling mechanisms involved. We will continue accomplishing our goals with close collaborations among investigators. Our multi-faceted approach incorporating molecular, biochemical, cellular, pharmacologic, and physiologic techniques in pigs, coronary vessels, single cells and subcellular components is unique in exercise science. This research will advance understanding of cellular/molecular mechanisms for coronary adaptations and likely reveal new and/or improved methods for prevention and treatment of CHD.