• Neil M Goldenberg, Liming Wang, Hannes Ranke, Wolfgang Liedtke, Arata Tabuchi, and Wolfgang M Kuebler.
• 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.).
• Anesthesiology. 2015 Jun 1;122(6):1338-48.

BackgroundHypoxic 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.MethodsHPV 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.ResultsThe 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.ConclusionTRPV4 plays a critical role in HPV, potentially via cooperation with TRPC6.

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