VASCULAR BIOLOGY: EXERCISE TRAINING AND CORONARY DISEASE

这本PPG的中心主题是运动训练(EX)通过有益于冠状动脉平滑肌(CSM)和内皮细胞的功能和表型的改变来治疗和减缓冠心病(CHD)的发展。我们有三个主要目标：1)阐明调节CSM和内皮的细胞/分子机制；2)确定EX诱导的血管阻力和通透性控制变化的机制；3)将对血管生物学和适应机制的了解应用到CHD(饮食诱导的高脂血症)模型中。我们的工作揭示了EX在组织和细胞/分子水平上引起的冠状动脉功能改变的重要特征。我们将用一种综合的实验方法来检验关于这些适应性机制的假说，以检查整个冠脉树的功能。第一个项目验证了这样的假设，即EX增加了CSM L型VGCC的数量和/或活性，并且张力增加是由EX-CSM中钙内流和钾电流的相互作用引起的。项目2验证了这样一种假说：EX通过改变腺苷(ADO)和内皮素-1(ET-1)的CSM受体信号机制，从而改变CSM的ADO转运体，从而改变腺苷(ADO)和内皮素-1(ET-1)的ADO机制，从而通过K通道的代谢和受体调节改变CSM ADO转运体，从而改变ADO的敏感性。项目3测试了这样的假设，即EX增加了编码内皮衍生介质和血管抗氧化系统的基因的表达，并且动脉大小、位置和机械力影响EX对内皮表型的影响。项目4测试了ADO导致EX后通透性和交换增加背后的NO依赖机制的假说，并将测试关于冠状动脉微血管中形成交换屏障的结构及其信号机制的假说。我们将继续在调查人员的密切合作下实现我们的目标。我们的多方面方法融合了分子、生化、细胞、药理学和生理学技术，在猪的冠状动脉、单细胞和亚细胞成分中是独一无二的。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冠心病的新的和/或改进的方法。

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.