{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T04:58:21Z","timestamp":1781499501740,"version":"3.54.1"},"reference-count":34,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2015,10,22]],"date-time":"2015-10-22T00:00:00Z","timestamp":1445472000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Metabolites of the endocannabinoid, 2\u2010arachidonoylglycerol (2\u2010AG) have been postulated to act as endogenous activators of TRPV4, a Ca<jats:sup>2+<\/jats:sup>\u2010permeable cation channel that plays a critical role in endothelium\u2010dependent relaxation. However, it is unclear if TRPV4 contributes to the vascular actions of 2\u2010AG.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Isometric tension recording of rat small mesenteric arteries and aortae were used to assess the effect of 2\u2010AG and the synthetic TRPV4 activator, GSK1016790A (GSK) on vascular reactivity. Changes in intracellular Ca<jats:sup>2+<\/jats:sup> concentration and single\u2010channel currents were measured in TRPV4\u2010expressing human coronary endothelial cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In mesenteric arteries, endothelium\u2010dependent relaxation to both 2\u2010AG and GSK was attenuated by structurally distinct TRPV4 antagonists, HC067047, RN1734 and ruthenium red. The responses were inhibited by K<jats:sub>Ca<\/jats:sub> inhibitors (apamin + charybdotoxin) and a gap junction inhibitor (18\u03b1\u2010glycyrrhetinic acid). In contrast to GSK, 2\u2010AG elicited considerable relaxation independently of the endothelium or TRPV4. Inhibition of 2\u2010AG metabolism via monoacylglycerol lipase and COX (by MAFP and indomethacin) caused potentiation, while cytochrome P450 and lipoxygenase inhibitors had no effect on 2\u2010AG relaxation. In coronary endothelial cells, 2\u2010AG (with and without MAFP) induced HC067047\u2010sensitive increases in intracellular Ca<jats:sup>2+<\/jats:sup> concentration. 2\u2010AG also increased TRPV4 channel opening in inside\u2010out patches. However, in aortae, GSK induced a relaxation sensitive to HC067047 and ruthenium red, whereas 2\u2010AG induced contractions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>These data suggest that 2\u2010AG can directly activate endothelial TRPV4, which partly contributes to the relaxant response to 2\u2010AG. However, the functional role of TRPV4 is highly dependent on the vascular region.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13312","type":"journal-article","created":{"date-parts":[[2015,8,21]],"date-time":"2015-08-21T05:51:28Z","timestamp":1440136288000},"page":"5251-5264","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Role of endothelial TRPV4 channels in vascular actions of the endocannabinoid, 2\u2010arachidonoylglycerol"],"prefix":"10.1111","volume":"172","author":[{"given":"W S V","family":"Ho","sequence":"first","affiliation":[{"name":"Vascular Biology Research Centre, Institute of Cardiovascular and Cell Sciences St George's University of London  Cranmer Terrace London SW17 0RE UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Center Medical College of Wisconsin  Milwaukee WI 53226 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