TRPV4 Is Required for Hypoxic Pulmonary Vasoconstriction. (June 2015)

• Record Type: Journal Article
• Authors: Goldenberg, Neil M.; Wang, Liming; Ranke, Hannes; Liedtke, Wolfgang; Tabuchi, Arata; Kuebler, Wolfgang M.
• Is Part Of: Anesthesiology. Volume 122:Number 6(2015)
• Publication Date: 2015-06
• Subjects: Anesthesiology -- Periodicals; Anesthetics -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1097/ALN.0000000000000647
• Languages: English
• ISSNs: 0003-3022

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background:</title> <p>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<sup>2+</sup> and contractile response to hypoxia. In this study, the authors probed the role of the TRP family member, TRPV4, in HPV.</p> </sec> <sec> <title>Methods:</title> <p>HPV was assessed by using isolated perfused mouse lungs or by intravital microscopy to directly visualize pulmonary arterioles in mice. <italic>In vitro</italic> experiments were performed in primary human PASMC.</p> </sec> <sec> <title>Results:</title> <p>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 (<italic>Trpv4</italic><sup><italic>−/−</italic></sup>) (3.4 ± 0.5 mmHg; n = 7 each). Functionally, <italic>Trpv4</italic><sup><italic>−/−</italic></sup> mice displayed an exaggerated hypoxemia after regional airway occlusion (p<sub>a</sub>O<sub>2</sub> 71% of baseline ± 2 <italic>vs</italic>. 85 ± 2%; n = 5). Direct visualization of pulmonary arterioles by intravital microscopy revealed a 66% reduction in HPV in <italic>Trpv4</italic><sup><italic>−/−</italic></sup> mice. In human PASMC, inhibition of TRPV4 blocked the hypoxia-induced Ca<sup>2+</sup> 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<sup>2+</sup> influx in response to the agonist, 11, 12-epoxyeicosatrienoic acid.</p> </sec> <sec> <title>Conclusion:</title> <p>TRPV4 plays a critical role in HPV, potentially <italic>via</italic> cooperation with TRPC6.</p> </sec> </abstract>