1. Hydrogen sulfide-induced vasodilation mediated by endothelial TRPV4 channels
- Author
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Benjimen R. Walker, Nancy L. Kanagy, Jessica M. Osmond, and Jay S. Naik
- Subjects
Male ,0301 basic medicine ,TRPV4 ,BK channel ,Endothelium ,Physiology ,Hydrogen sulfide ,TRPV Cation Channels ,Vasodilation ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Leucine ,Physiology (medical) ,medicine ,Animals ,Hydrogen Sulfide ,Large-Conductance Calcium-Activated Potassium Channels ,Sulfonamides ,biology ,Gasotransmitters ,Endothelial Cells ,Mesenteric Arteries ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Anesthesia ,Call for Papers ,biology.protein ,Biophysics ,Endothelium, Vascular ,Cardiology and Cardiovascular Medicine - Abstract
Hydrogen sulfide (H2S) 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 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 TRPV4 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 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.
- Published
- 2016