Hydrogen sulfide-induced vasodilation mediated by endothelial TRPV4 channels.

Hydrogen sulfide (HS) is a recently described gaseous vasodilator produced within the vasculature by the enzymes cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase. Previous data demonstrate that endothelial cells (EC) are the source of endogenous HS production and are required for HS-induced dilation. However, the signal transduction pathway activated by HS within EC has not been elucidated. TRPV4 and large-conductance Ca-activated K channels (BK channels) are expressed in EC. HS-induced dilation is inhibited by luminal administration of iberiotoxin and disruption of the endothelium. Calcium influx through TRPV4 may activate these endothelial BK channels (eBK). We hypothesized that HS-mediated vasodilation involves activation of TRPV4 within the endothelium. In pressurized, phenylephrine-constricted mesenteric arteries, HS elicited a dose-dependent vasodilation blocked by inhibition of TRPV4 channels (GSK2193874A, 300 nM). HS (1 μM) increased TRPV4-dependent (1.8-fold) localized calcium events in EC of pressurized arteries loaded with fluo-4 and Oregon Green. In pressurized EC tubes, HS (1 μM) and the TRPV4 activator, GSK101679A (30 nM), increased calcium events 1.8- and 1.5-fold, respectively. HS-induced an iberiotoxin-sensitive outward current measured using whole cell patch-clamp techniques in freshly dispersed EC. HS increased K currents from 10 to 30 pA/pF at +150 mV. Treatment with NaS increased the level of sulfhydration of TRPV4 channels in aortic ECs. These results demonstrate that HS-mediated vasodilation involves activation of TRPV4-dependent Ca influx and BK channel activation within EC. Activation of TRPV4 channels appears to cause calcium events that result in the opening of eBK channels, endothelial hyperpolarization, and subsequent vasodilation.