S7-1 Vascular sulfide metabolism during ischemia

Abstract

Hydrogen sulfide is well known to regulate multiple physiological aspects of vascular function including vasodilation, inflammation, and growth responses that may become dysfunctional during ischemia. However, specific sulfide metabolism responses during chronic vascular ischemia remain poorly understood. Recent work from our laboratory reveals that permanent vascular ischemia due to ligation and surgical removal results in a rapid increase in cystathionine gamma lyase (CSE) expression along with increased hydrogen sulfide bioavailability within ischemic tissues that prefaces restoration of ischemic tissue blood flow. Importantly, as tissue perfusion is restored, expression of CSE is reduced back to basal levels along with hydrogen sulfide metabolites. Consistent with these observations, genetic deletion of CSE significantly blunts ischemic tissue vascular remodeling responses necessary for tissue reperfusion. Whereas, transgenic vascular endothelial cell CSE expression significantly augments ischemic vascular remodeling responses leading to tissue reperfusion. These responses invoke increased nitric oxide formation and vascular endothelial cell growth factor production that are critical requirements for chronic ischemic vascular remodeling. Together, these data reveal that progressive induction of vascular sulfide metabolism during chronic ischemia is an important physiological adaptive response.