title: Hydrogen sulfide-induced vasodilation mediated by endothelial TRPV4 channels.
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.
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, New Mexico jnaik@salud.unm.edu.
authors.forename: Jay S
authors.identifier: 0000-0002-5725-4664
authors.initials: JS
authors.lastname: Naik
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Osmond
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Benjimen R
authors.initials: BR
authors.lastname: Walker
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Kanagy
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D064426:Gasotransmitters / Q000494:pharmacology*; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D064426:Gasotransmitters; D051036:Large-Conductance Calcium-Activated Potassium Channels; C530602:N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide; D013449:Sulfonamides; D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat; D007930:Leucine; D006862:Hydrogen Sulfide
keywords: BK channel; TRPV4; endothelium; hydrogen sulfide; vasodilation