TRPV4 (Transient Receptor Potential Vanilloid 4) Mediates Endothelium-Dependent Contractions in the Aortas of Hypertensive Mice

作者：Zhang, Peng; Sun, Chunyuan; Li, Hongjuan; Tang, Chunlei; Kan, Hao; Yang, Zhenyu; Mao, Aiqin; Ma, Xin^*

来源：Hypertension, 2018, 71(1): 134-142.

DOI：10.1161/HYPERTENSIONAHA.117.09767

• acetylcholine
• aorta
• cyclooxygenase 2
• endothelium
• hypertension

The role of TRPV4 (transient receptor potential vanilloid 4) in regulating vascular contraction in hypertensive mice is poorly established. We tested the hypothesis that TRPV4 regulates endothelium-dependent contractions in aortas from hypertensive mice through the activation of cytosolic cPLA(2) (phospholipase A(2)) and COX2 (cyclooxygenase 2) and identified the possible endothelium-derived contracting factor generated by COX2. Using myography, we demonstrated that GSK1016790A (a TRPV4 agonist) and acetylcholine (ACh) trigger endothelium-dependent contractions in aortas from hypertensive mice, and the contractions were abolished with TRPV4 deletion. PLA(2) assay and Western blotting showed that cPLA(2) activity was higher in salt-induced hypertension and HC067047 or a Ca2+ chelator inhibited cPLA(2) activity. Contractions induced by TRPV4 and ACh were inhibited by the cPLA(2) inhibitor or removal of extracellular Ca2+. COX2 expression was enhanced in the endothelium from hypertensive mice and contractions induced by TRPV4 or ACh were inhibited by the COX2 inhibitor. Enzyme immunoassay showed that the release of prostaglandin F-2 (PGF(2)) was increased in hypertensive mice. GSK1016790A or ACh triggered the release of PGF(2) and this was inhibited by HC067047, the cPLA(2) inhibitor, and COX2 inhibitor. GSK1016790A, ACh, and PGF(2) induced contractions were significantly reduced by S18886 in salt-induced hypertensive mice. The present study demonstrates that PGF(2) generated by COX2 in the endothelium is the most likely endothelium-derived contracting factor underlying endothelium-dependent, TRPV4-mediated contraction in hypertensive mice. This contraction involved increased intracellular Ca2+ concentrations and cPLA(2) activity. These results suggested an important role of TRPV4 in endothelium-dependent contraction in mice during hypertension.

• 出版日期2018-1
• 单位江南大学