Hydrogen sulfide synthesis and metabolism is an important participant in cardiovascular health and function. Specifically, our laboratory has shown that cystathionine g-lyase (CSE) expression and function play a critical role in ischemic vascular remodeling responses of arteriogenesis and angiogenesis. Moreover, our group has revealed important chemical biology and pathophysiological relationships between sulfide and nitric oxide metabolites in clinical vascular disease conditions, which may be important for cooperative regulation of ischemic vascular remodeling. However, numerous molecular and cellular mechanisms remain completely unknown in these responses including: the role of specific cell populations in producing discrete sulfide species during ischemic vascular remodeling, how different sulfide metabolites modulate nitric oxide (NO) bioavailability through various biochemical pathways, and mechanisms regulating rapid increases in CSE activity dependent sulfide metabolite bioavailability during hypoxia. This application will address these important unknown areas using novel tissue specific CSE mutant mouse models, cutting edge analytical chemistry measurement methods of sulfide and NO species, cellular and molecular methods to discover posttranslational regulation of CSE protein activity in response to hypoxia, and clinical tissue specimens to better understand persulfide and polysulfide during vascular remodeling and disease. Using the models and tools above, this proposal will examine the hypothesis that endothelial cell and monocyte CSE dependent polysulfide formation differentially regulates ischemic vascular remodeling and NO bioavailability.
Three specific aims will be pursued to test the hypothesis including: 1) determine the mechanisms of endothelial CSE regulation of ischemic vascular remodeling and how it controls vascular cell NO bioavailability, 2) determine the mechanisms of monocyte CSE regulation of arteriogenesis, and 3) determine mechanisms of CSE activity and expression in experimental models and clinical specimens. Completion of this project will provide crucial new basic insight that is not currently available regarding mechanisms of CSE regulation and polysulfide effects on cell biology during ischemic vascular remodeling.
Peripheral ischemic vascular disease (e.g. Peripheral Arterial Disease (PAD) and Critical Limb Ischemia (CLI)) are vascular disorders associated with reduced tissue blood flow to organs and extremities, which results in serious complications. There is an increasing prevalence of peripheral vascular diseases presenting significant health burdens worldwide. No FDA approved therapeutic is available to effectively promote ischemic revascularization of chronically ischemic tissue. The objectives of this project are to advance the field?s understanding of CSE enzyme regulation and function of ischemic vascular remodeling, which is essential for understanding and improving effective therapeutic modalities for prevention of ischemic cardiovascular disease.