title: Role of endothelial TRPV4 channels in vascular actions of the endocannabinoid, 2-arachidonoylglycerol.
abstract: OBJECTIVE
  Metabolites of the endocannabinoid, 2-arachidonoylglycerol (2-AG) have been postulated to act as endogenous activators of TRPV4, a Ca(2+) -permeable cation channel that plays a critical role in endothelium-dependent relaxation. However, it is unclear if TRPV4 contributes to the vascular actions of 2-AG.
  
  
  METHODS
  Isometric tension recording of rat small mesenteric arteries and aortae were used to assess the effect of 2-AG and the synthetic TRPV4 activator, GSK1016790A (GSK) on vascular reactivity. Changes in intracellular Ca(2+) concentration and single-channel currents were measured in TRPV4-expressing human coronary endothelial cells.
  
  
  RESULTS
  In mesenteric arteries, endothelium-dependent relaxation to both 2-AG and GSK was attenuated by structurally distinct TRPV4 antagonists, HC067047, RN1734 and ruthenium red. The responses were inhibited by KCa inhibitors (apamin + charybdotoxin) and a gap junction inhibitor (18α-glycyrrhetinic acid). In contrast to GSK, 2-AG elicited considerable relaxation independently of the endothelium or TRPV4. Inhibition of 2-AG metabolism via monoacylglycerol lipase and COX (by MAFP and indomethacin) caused potentiation, while cytochrome P450 and lipoxygenase inhibitors had no effect on 2-AG relaxation. In coronary endothelial cells, 2-AG (with and without MAFP) induced HC067047-sensitive increases in intracellular Ca(2+) concentration. 2-AG also increased TRPV4 channel opening in inside-out patches. However, in aortae, GSK induced a relaxation sensitive to HC067047 and ruthenium red, whereas 2-AG induced contractions.
  
  
  CONCLUSIONS
  These data suggest that 2-AG can directly activate endothelial TRPV4, which partly contributes to the relaxant response to 2-AG. However, the functional role of TRPV4 is highly dependent on the vascular region.
authors: Vascular Biology Research Centre, Institute of Cardiovascular and Cell Sciences, St George's University of London, Cranmer Terrace, London, SW17 0RE, UK.
authors: W S V
authors: WS
authors: Ho
authors: Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors: X
authors: X
authors: Zheng
authors: Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors: D X
authors: DX
authors: Zhang
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D003331:Coronary Vessels / Q000166:cytology; D063388:Endocannabinoids / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D005989:Glycerides / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D017208:Rats, Wistar; D050916:TRPV Cation Channels / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D005989:Glycerides; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; C486577:Trpv4 protein, rat; C094503:glyceryl 2-arachidonate