Hydrogen sulfide and vascular remodeling

描述(由申请人提供)：实验证据表明，气体传递剂硫化氢在心血管系统中发挥着重要作用，特别是在组织缺血期间。然而，血管内硫化氢的特定细胞来源、靶点和机制仍然很大程度上是未知的。我们实验室和其他实验室的工作表明，硫化氢对慢性组织缺血具有保护作用，慢性组织缺血涉及血管重建反应增加，如血管生成。重要的是，关于硫化氢如何在体内或体外调节缺血性血管重塑的机制信息很少。这项应用中的数据揭示了一项新的发现，即由胱硫醚裂解酶(CSE)产生的硫化氢选择性地增强了缺血组织亚硝酸盐还原为NO，从而介导了涉及HIF-1活性和VEGF表达的血管生成活性的增加。这一方案中的实验将通过以下假设确定这些新结果的分子机制：内皮细胞CSE依赖的硫化氢生成增加缺血亚硝酸盐还原为NO，从而增加缺血血管重塑。这一假说将通过追求三个具体目标来验证，包括：1)确定内皮细胞CSE表达如何调节缺血血管重构反应，2)确定硫化氢增加缺血组织中NO产生的机制以及这如何调节HIF-1“活性和血管内皮生长因子的表达，以及3)确定内皮细胞CSE依赖的硫化氢对糖尿病缺血血管重构反应的影响。该项目的成功完成将极大地促进对血管系统中硫化氢生物学领域的了解，提供关于硫化氢-NO途径相互作用的明确机制信息，并确定治疗缺血性血管疾病的新方法。

DESCRIPTION (provided by applicant): Experimental evidence is emerging that the gasotransmitter hydrogen sulfide serves an important role in the cardiovascular system especially during tissue ischemia. However, specific cellular sources, targets, and mechanisms of hydrogen sulfide within the vasculature remain largely unknown. Work from our lab and others demonstrate that hydrogen sulfide is protective against chronic tissue ischemia, which involves increased vascular remodeling responses such as angiogenesis. Importantly, very little mechanistic information exists regarding how hydrogen sulfide modulates ischemic vascular remodeling in vivo or in vitro. Data in this application reveals a novel finding that hydrogen sulfide emanating from cystathionine !-lyase (CSE) selectively augments ischemic tissue nitrite reduction to NO that mediates increased angiogenic activity involving HIF-1" activity and VEGF expression. Experiments in this proposal will determine molecular mechanisms for these novel results through the hypothesis that endothelial cell CSE dependent hydrogen sulfide generation augments ischemic nitrite reduction to NO that increases ischemic vascular remodeling. The hypothesis will be examined through the pursuit of three specific aims including: 1) determine how endothelial cell CSE expression regulates ischemic vascular remodeling responses, 2) determine the mechanisms by which hydrogen sulfide increases NO generation in ischemic tissue and how this regulates HIF-1" activity and VEGF expression, and 3) determine the effect of endothelial cell CSE dependent hydrogen sulfide on diabetic ischemic vascular remodeling responses. Successful completion of this project will significantly advance the fields understanding of hydrogen sulfide biology in the vascular system, provide clear mechanistic information on hydrogen sulfide-NO pathway interactions, and identify novel approaches for ischemic vascular disease therapy.