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Role of endothelial TRPV4 channels in vascular actions of the endocannabinoid, 2-arachidonoylglycerol. Br J Pharmacol 2015 Nov;172(22):5251-64

Date

08/22/2015

Pubmed ID

26294342

Pubmed Central ID

PMC4950792

DOI

10.1111/bph.13312

Scopus ID

2-s2.0-84956789081   16 Citations

Abstract

BACKGROUND AND PURPOSE: 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.

EXPERIMENTAL APPROACH: 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.

KEY 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 AND IMPLICATIONS: 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.

Author List

Ho WS, Zheng X, Zhang DX

Author

David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Arachidonic Acids
Cannabinoid Receptor Agonists
Coronary Vessels
Endocannabinoids
Endothelial Cells
Glycerides
Humans
In Vitro Techniques
Male
Mesenteric Arteries
Rats, Wistar
TRPV Cation Channels
Vasodilation
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