Vascular Biology of Hydrogen Sulfide

长期以来，硫化氢一直被认为是一种有毒气体，最近在哺乳动物中被证明是一种神经递质和局部信号分子。该实验室(NSF IBN-0235223)最近的工作表明，硫化氢影响所有脊椎动物的心血管功能，并导致了一种新的假说，即硫化氢是迄今难以捉摸的氧“传感器”，在全身血管中产生缺氧性松弛，在肺血管中产生缺氧性收缩。这个项目将研究硫化氢如何调节血管中的缺氧反应，以及这种信号是如何转化为收缩或松弛的。它还将确定硫化氢在原始脊椎动物一般心血管功能中的作用。对单个平滑肌细胞的电生理学研究，对分离血管的生化和生物物理研究，以及对未麻醉动物的完整心血管测量，将在从原始八目鳗到哺乳动物的各种脊椎动物上进行。这些研究将首次对这一新假说进行全面调查，该假说认为硫化氢是血管中氧气“感应”的关键成分，并将确定硫化氢在脊椎动物心血管系统中的系统起源和影响。这些结果将对所有脊椎动物的生理学产生广泛的影响，解决长期存在的血管氧感应难题，并将为研究硫化氢在脊椎动物心血管系统中的整合作用提供一个进化窗口。这项工作也与环境生物学有关，因为硫化氢通常是工农业活动的副产品，对水生脊椎动物有潜在的削弱作用。此外，该项目将支持下一代“广谱”比较生理学家的教育，因为它将提供从分子生物学到全动物生理学的综合培训计划。

Long known as a toxic gas, hydrogen sulfide (H2S) has recently been shown in mammals to serve as a neurotransmitter and local signaling molecule. Recent work in this laboratory (NSF IBN-0235223) suggested that H2S impacts cardiovascular function in all vertebrates and it also led to the novel hypothesis that H2S is the heretofore elusive oxygen "sensor" producing hypoxic relaxation in systemic vessels and hypoxic constriction in pulmonary vessels. This project will examine how H2S mediates hypoxic responses in blood vessels and how this signal is transduced into contraction or relaxation. It will also determine the role of H2S in general cardiovascular function in primitive vertebrates. Electrophysiological studies on single smooth muscle cells, biochemical and biophysical studies of isolated blood vessels, and complete cardiovascular measurements on unanesthetized animals will be performed on a variety of vertebrates, from primitive hagfish to mammals. These studies will provide the first comprehensive investigation of the novel hypothesis that H2S is the key component in oxygen "sensing" in blood vessels and they will identify the phylogenetic origin and impact of H2S in the vertebrate cardiovascular system. The results will have broad implications for all of vertebrate physiology by resolving the long-standing conundrum of vascular oxygen sensing and they will provide an evolutionary window into the integrative role of H2S in the vertebrate cardiovascular system. This work is also relevant to environmental biology because H2S is often a byproduct of industrial and agricultural activity and it is potentially debilitating to aquatic vertebrates. In addition, this project will support the education of the next generation of "broad spectrum" comparative physiologists as it will provide an integrative training program from molecular biology to whole-animal physiology.