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TRPV4-mediated endothelial Ca2+ influx and vasodilation in response to shear stress. Am J Physiol Heart Circ Physiol 2010 Feb;298(2):H466-76

Date

12/08/2009

Pubmed ID

19966050

Pubmed Central ID

PMC2822567

DOI

10.1152/ajpheart.00854.2009

Scopus ID

2-s2.0-74949090413   175 Citations

Abstract

The transient receptor potential vallinoid type 4 (TRPV4) channel has been implicated in the endothelial shear response and flow-mediated dilation, although the precise functions of this channel remain poorly understood. In the present study, we investigated the role of TRPV4 in shear stress-induced endothelial Ca(2+) entry and the potential link between this signaling response and relaxation of small resistance arteries. Using immunohistochemical analysis and RT-PCR, we detected strong expression of TRPV4 protein and mRNA in the endothelium in situ and endothelial cells freshly isolated from mouse small mesenteric arteries. The selective TRPV4 agonist GSK1016790A increased endothelial Ca(2+) and induced potent relaxation of small mesenteric arteries from wild-type (WT) but not TRPV4(-/-) mice. Luminal flow elicited endothelium-dependent relaxations that involved both nitric oxide and EDHFs. Both nitric oxide and EDHF components of flow-mediated relaxation were markedly reduced in TRPV4(-/-) mice compared with WT controls. Using a fura-2/Mn(2+) quenching assay, shear was observed to produce rapid Ca(2+) influx in endothelial cells, which was markedly inhibited by the TRPV4 channel blocker ruthenium red and TRPV4-specific short interfering RNA. Flow elicited a similar TRPV4-mediated Ca(2+) entry in HEK-293 cells transfected with TRPV4 channels but not in nontransfected cells. Collectively, these data indicate that TRPV4 may be a potential candidate of mechanosensitive channels in endothelial cells through which the shear stimulus is transduced into Ca(2+) signaling, leading to the release of endothelial relaxing factors and flow-mediated dilation of small resistance arteries.

Author List

Mendoza SA, Fang J, Gutterman DD, Wilcox DA, Bubolz AH, Li R, Suzuki M, Zhang DX

Authors

David D. Gutterman MD Sr Associate Director, Professor in the Medicine department at Medical College of Wisconsin
David A. Wilcox PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
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
Biomechanical Phenomena
Calcium
Calcium Signaling
Cell Line
Endothelium, Vascular
Humans
Kidney
Leucine
Male
Mesenteric Arteries
Mice
Mice, Knockout
Models, Animal
Nitric Oxide
Stress, Mechanical
Sulfonamides
TRPV Cation Channels
Transfection
Vasodilation
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a