ISH NIA PS 01-06 Downregulation of endothelial TRPV4 channel contributes to the reduced endothelium-dependent hyperpolarization in genetically hypertensive rats

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Endothelium-dependent hyperpolarization (EDH)-mediated responses are decreased in hypertension. However, the underlying mechanisms have not yet been determined. Several recent studies have suggested that Ca2+ influx through endothelial transient receptor potential vanilloid 4 channel (TRPV4) plays a role in EDH-mediated hyperpolarization via the downstream activation of small- and intermediate-conductance of Ca2+-activated K+ channels (SKCa and IKCa). The present study was designed to elucidate whether the impairment of EDH-mediated responses in hypertension is attributable to the dysfunction of TRPV4 and/or KCa.

Design and Method:

Conventional electrophysiological and molecular biology techniques were used in isolated superior mesenteric arteries of 20-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar-Kyoto (WKY) rats.


In the WKY mesenteric arteries, acetylcholine (ACh)-induced, EDH-mediated relaxations were reduced by a combination of KCa blockers (apamin plus TRAM-34), and by the blockade of TRPV4 with the selective antagonist RN-1734 or HC-067047. In the SHRSP mesenteric arteries, the ACh-induced, EDH-mediated hyperpolarization and relaxation were significantly smaller compared with those of WKY. GSK1016790A, a selective TRPV4 activator, evoked robust hyperpolarization and relaxation in WKY arteries. In contrast, in SHRSP arteries, the GSK1016790A-evoked hyperpolarization was small and relaxation was absent. Hyperpolarization and relaxation in response to CyPPA, a selective SKCa activator, were marginally decreased in SHRSP arteries compared with those of WKY. On the other hand, hyperpolarization and relaxation in response to 1-EBIO, a selective IKCa activator, and to levcromakalim, an ATP-sensitive K+ channel opener, were comparable between groups. The expression of endothelial TRPV4 and SKCa protein were significantly decreased in the SHRSP mesenteric arteries compared to those of WKY.


These findings suggest that downregulation of endothelial TRPV4 predominantly underpins the reduced ACh-induced, EDH-mediated responses in mesenteric arteries of SHRSP.

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