Hydrogen sulfide (H2S) is a recently described gaseous vasodilator produced within the vasculature by the enzymes cystathionine γ-lyase and 3-mercaptopyruvate sulfurtansferase. Previous data demonstrate that endothelial cells (EC) are the source of endogenous H2S production and are required for H2S-induced dilation. However, the signal transduction pathway activated by H2S within EC has not been elucidated. TRPV4 and large conductance Ca2+-activated K channels (BK channels) are expressed in EC. H2S-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 H2S-mediated vasodilation involves activation of TPRV4 within the endothelium. In pressurized, phenylephrine-constricted mesenteric arteries, H2S elicited a dose-dependent vasodilation blocked by inhibition of TRPV4 channels (GSK2193874A, 300 nM). H2S (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, H2S (1 µM) and the TRPV4 activator, GSK101679A (30 nM) increased calcium events 1.8 and 1.5 fold, respectively. H2S-induced an iberiotoxin-sensitive outward current measured using whole-cell patch clamp techniques in freshly dispersed EC. H2S increased K+ currents from 10 pA/pF to 30 pA/pF at +150 mV. Treatment with Na2S increased the level of sulfhydration of TRPV4 channels in aortic ECs. These results demonstrate that H2S-mediated vasodilation involves activation of TRPV4-dependent Ca2+ 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.
- Hydrogen Sulfide
- BK channel
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology