{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T11:38:48Z","timestamp":1791113928037,"version":"4.1.0"},"reference-count":76,"publisher":"American Physiological Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2013,10,1]]},"abstract":"<jats:p> Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive channel in pulmonary arterial smooth muscle cells (PASMCs). Its upregulation by chronic hypoxia is associated with enhanced myogenic tone, and genetic deletion of trpv4 suppresses the development of chronic hypoxic pulmonary hypertension (CHPH). Here we further examine the roles of TRPV4 in agonist-induced pulmonary vasoconstriction and in the enhanced vasoreactivity in CHPH. Initial evaluation of TRPV4-selective antagonists HC-067047 and RN-1734 in KCl-contracted pulmonary arteries (PAs) of trpv4<jats:sup> \u2212\/\u2212<\/jats:sup> mice found that submicromolar HC-067047 was devoid of off-target effect on pulmonary vasoconstriction. Inhibition of TRPV4 with 0.5 \u03bcM HC-067047 significantly reduced the sensitivity of serotonin (5-HT)-induced contraction in wild-type (WT) PAs but had no effect on endothelin-1 or phenylephrine-activated response. Similar shift in the concentration-response curve of 5-HT was observed in trpv4<jats:sup> \u2212\/\u2212<\/jats:sup> PAs, confirming specific TRPV4 contribution to 5-HT-induced vasoconstriction. 5-HT-induced Ca<jats:sup>2+<\/jats:sup> response was attenuated by HC-067047 in WT PASMCs but not in trpv4<jats:sup> \u2212\/\u2212<\/jats:sup> PASMCs, suggesting TRPV4 is a major Ca<jats:sup>2+<\/jats:sup> pathway for 5-HT-induced Ca<jats:sup>2+<\/jats:sup> mobilization. Nifedipine also attenuated 5-HT-induced Ca<jats:sup>2+<\/jats:sup> response in WT PASMCs but did not cause further reduction in the presence of HC-067047, suggesting interdependence of TRPV4 and voltage-gated Ca<jats:sup>2+<\/jats:sup> channels in the 5-HT response. Chronic exposure (3\u20134 wk) of WT mice to 10% O<jats:sub>2<\/jats:sub> caused significant increase in 5-HT-induced maximal contraction, which was partially reversed by HC-067047. In concordance, the enhancement of 5-HT-induced contraction was significantly reduced in PAs of CH trpv4<jats:sup> \u2212\/\u2212<\/jats:sup> mice and HC-067047 had no further effect on the 5-HT induced response. These results suggest unequivocally that TRPV4 contributes to 5-HT-dependent pharmaco-mechanical coupling and plays a major role in the enhanced pulmonary vasoreactivity to 5-HT in CHPH. <\/jats:p>","DOI":"10.1152\/ajpcell.00099.2013","type":"journal-article","created":{"date-parts":[[2013,6,6]],"date-time":"2013-06-06T03:57:50Z","timestamp":1370491070000},"page":"C704-C715","source":"Crossref","is-referenced-by-count":105,"title":["TRPV4 channel contributes to serotonin-induced pulmonary vasoconstriction and the enhanced vascular reactivity in chronic hypoxic pulmonary hypertension"],"prefix":"10.1152","volume":"305","author":[{"given":"Yang","family":"Xia","sequence":"first","affiliation":[{"name":"Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China;"},{"name":"Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Fu","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxing","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omkar","family":"Paudel","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoxi","family":"Cai","sequence":"additional","affiliation":[{"name":"Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Liedtke","sequence":"additional","affiliation":[{"name":"Center for Translational Neuroscience, Duke University, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S. 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