title: TRPV4 Is Required for Hypoxic Pulmonary Vasoconstriction.
abstract: BACKGROUND
  Hypoxic pulmonary vasoconstriction (HPV) is critically important in regionally heterogeneous lung diseases by directing blood toward better-oxygenated lung units, yet the molecular mechanism of HPV remains unknown. Transient receptor potential (TRP) channels are a large cation channel family that has been implicated in HPV, specifically in the pulmonary artery smooth muscle cell (PASMC) Ca and contractile response to hypoxia. In this study, the authors probed the role of the TRP family member, TRPV4, in HPV.
  
  
  METHODS
  HPV was assessed by using isolated perfused mouse lungs or by intravital microscopy to directly visualize pulmonary arterioles in mice. In vitro experiments were performed in primary human PASMC.
  
  
  RESULTS
  The hypoxia-induced pulmonary artery pressure increase seen in wild-type mice (5.6 ± 0.6 mmHg; mean ± SEM) was attenuated both by inhibition of TRPV4 (2.8 ± 0.5 mmHg), or in lungs from TRPV4-deficient mice (Trpv4) (3.4 ± 0.5 mmHg; n = 7 each). Functionally, Trpv4 mice displayed an exaggerated hypoxemia after regional airway occlusion (paO2 71% of baseline ± 2 vs. 85 ± 2%; n = 5). Direct visualization of pulmonary arterioles by intravital microscopy revealed a 66% reduction in HPV in Trpv4 mice. In human PASMC, inhibition of TRPV4 blocked the hypoxia-induced Ca influx and myosin light chain phosphorylation. TRPV4 may form a heteromeric channel with TRPC6 as the two channels coimmunoprecipitate from PASMC and as there is no additive effect of TRPC and TRPV4 inhibition on Ca influx in response to the agonist, 11,12-epoxyeicosatrienoic acid.
  
  
  CONCLUSIONS
  TRPV4 plays a critical role in HPV, potentially via cooperation with TRPC6.
authors: From the Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada (N.M.G.); the Keenan Research Centre at the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada (L.W., A.T., W.M.K.); Institute of Physiology, Charité-University Berlin, Berlin, Germany (H.R., W.M.K.); Duke Institute for Brain Sciences, Duke University, Durham, North Carolina (W.L.); German Heart Institute Berlin, Berlin, Germany (W.M.K.); and Departments of Physiology and Surgery, University of Toronto, Toronto, Ontario, Canada (W.M.K.).
authors: Neil M
authors: NM
authors: Goldenberg
authors: Liming
authors: L
authors: Wang
authors: Hannes
authors: H
authors: Ranke
authors: Wolfgang
authors: W
authors: Liedtke
authors: Arata
authors: A
authors: Tabuchi
authors: Wolfgang M
authors: WM
authors: Kuebler
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D021941:Caveolae / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D061810:One-Lung Ventilation; D011652:Pulmonary Circulation / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000187:drug effects* / Q000235:genetics; D051216:Toll-Like Receptor 6 / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014692:Ventilation-Perfusion Ratio
chemical_list: D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D002118:Calcium