TRPV4 channel contributes to serotonin-induced pulmonary vasoconstriction and the enhanced vascular reactivity in chronic hypoxic pulmonary hypertension

Yang Xia, Zhenzhen Fu, Jinxing Hu, Chun Huang, Omkar Paudel, Shaoxi Cai, Wolfgang Liedtke, James S.K. Sham

Research output: Contribution to journalArticle

Abstract

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-/- mice found that submicromolar HC-067047 was devoid of off-target effect on pulmonary vasoconstriction. Inhibition of TRPV4 with 0.5 μM 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 concentrationresponse curve of 5-HT was observed in trpv4-/- PAs, confirming specific TRPV4 contribution to 5-HT-induced vasoconstriction. 5-HT-induced Ca2+ response was attenuated by HC-067047 in WT PASMCs but not in trpv4-/- PASMCs, suggesting TRPV4 is a major Ca2+ pathway for 5-HT-induced Ca2+ mobilization. Nifedipine also attenuated 5-HT-induced Ca2+ response in WT PASMCs but did not cause further reduction in the presence of HC-067047, suggesting interdependence of TRPV4 and voltage-gated Ca2+ channels in the 5-HT response. Chronic exposure (3-4 wk) of WT mice to 10% O2 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-/- 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.

Original languageEnglish (US)
Pages (from-to)C704-C715
JournalAmerican Journal of Physiology - Cell Physiology
Volume305
Issue number7
DOIs
StatePublished - Oct 1 2013

Keywords

  • Chronic hypoxia
  • Pulmonary arteries
  • Pulmonary hypertension
  • Serotonin
  • TRPV4

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Fingerprint Dive into the research topics of 'TRPV4 channel contributes to serotonin-induced pulmonary vasoconstriction and the enhanced vascular reactivity in chronic hypoxic pulmonary hypertension'. Together they form a unique fingerprint.

  • Cite this