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CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction.

ABSTRACT: Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo. Ca(2+) mobilization and transient receptor potential canonical 6 (TRPC6) translocation were studied in human pulmonary (PASMCs) or coronary (CASMCs) artery smooth muscle cells. CFTR inhibition or deficiency diminished HPV and aggravated ventilation-perfusion mismatch. In PASMCs, hypoxia caused CFTR to interact with TRPC6, whereas CFTR inhibition attenuated hypoxia-induced TRPC6 translocation to caveolae and Ca(2+) mobilization. Ca(2+) mobilization by sphingosine-1-phosphate (S1P) was also attenuated by CFTR inhibition in PASMCs, but amplified in CASMCs. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, whereas exogenous nSMase caused TRPC6 translocation and vasoconstriction that were blocked by CFTR inhibition. nSMase- and hypoxia-induced vasoconstriction, yet not TRPC6 translocation, were blocked by inhibition or deficiency of sphingosine kinase 1 (SphK1) or antagonism of S1P receptors 2 and 4 (S1P2/4). S1P and nSMase had synergistic effects on pulmonary vasoconstriction that involved TRPC6, phospholipase C, and rho kinase. Our findings demonstrate a central role of CFTR and sphingolipids in HPV. Upon hypoxia, nSMase triggers TRPC6 translocation, which requires its interaction with CFTR. Concomitant SphK1-dependent formation of S1P and activation of S1P2/4 result in phospholipase C-mediated TRPC6 and rho kinase activation, which conjointly trigger vasoconstriction.

SUBMITTER: Tabeling C

PROVIDER: S-EPMC4386337 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction.

Tabeling Christoph C Yu Hanpo H Wang Liming L Ranke Hannes H Goldenberg Neil M NM Zabini Diana D Noe Elena E Krauszman Adrienn A Gutbier Birgitt B Yin Jun J Schaefer Michael M Arenz Christoph C Hocke Andreas C AC Suttorp Norbert N Proia Richard L RL Witzenrath Martin M Kuebler Wolfgang M WM

Proceedings of the National Academy of Sciences of the United States of America 20150317 13

Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse ...[more]

PMID: 25829545

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Project description:BackgroundHypoxic pulmonary vasoconstriction (HPV) optimizes the match between ventilation and perfusion in the lung by reducing blood flow to poorly ventilated regions. Sepsis and endotoxemia impair HPV. We previously showed that nitric oxide synthase 2 (NOS2) is required, but not sufficient, for the effect of endotoxin on HPV. The aim of the current study was to identify additional factors that might contribute to the impairment of HPV during endotoxemia.MethodsGene expression profiling was determined using pulmonary tissues from NOS2-deficient (NOS2-/-) and wild-type mice subjected to endotoxin or saline challenge (control). HPV was accessed as the percentage increase in left pulmonary vascular resistance (LPVR) in response to left main bronchus occlusion (LMBO) in wild-type mice.ResultsAmong the 22,690 genes analyzed, endotoxin induced a greater than three-fold increase in 59 and 154 genes in the lungs of wild-type and NOS2-/- mice, respectively. Of all the genes induced by endotoxin in wild-type mice, arginase 1 (Arg1) showed the greatest increase (16.3-fold compared to saline treated wild-type mice). In contrast, endotoxin did not increase expression of Arg1 in NOS2-/- mice. There was no difference in the endotoxin-induced expression of Arg2 between wild-type and NOS2-deficient mice. We investigated the role of arginase in HPV by treating the mice with normal saline or the arginase inhibitor Nω-hydroxy-nor-L-arginine (norNOHA). In control mice (in the absence of endotoxin) treated with normal saline, HPV was intact as determined by profound LMBO-induced increase in LPVR (121 ± 22% from baseline). During endotoxemia and treatment with normal saline, HPV was impaired compared to normal saline treated control mice (33 ± 9% vs. 121 ± 22%, P < 0.05). HPV was restored in endotoxin-exposed mice after treatment with the arginase inhibitor norNOHA as shown by the comparison to endotoxemic mice treated with normal saline (113 ± 29% vs, 33 ± 9%, P < 0.05) and to control mice treated with normal saline (113 ± 29% vs, 121 ± 22%, P = 0.97).ConclusionsThe results of this study suggest that endotoxemia induces Arg1 and that arginase contributes to the endotoxin-induced impairment of HPV in mice.

Project description:AimsHypoxic pulmonary vasoconstriction (HPV) is a physiological response to alveolar hypoxia that diverts blood flow from poorly ventilated to better aerated lung areas to optimize ventilation-perfusion matching. Yet, the exact sensory and signalling mechanisms by which hypoxia triggers pulmonary vasoconstriction remain incompletely understood. Recently, ATP release via pannexin 1 (Panx1) and subsequent signalling via purinergic P2Y receptors has been identified as regulator of vasoconstriction in systemic arterioles. Here, we probed for the role of Panx1-mediated ATP release in HPV and chronic hypoxic pulmonary hypertension (PH).Methods and resultsPharmacological inhibition of Panx1 by probenecid, spironolactone, the Panx1 specific inhibitory peptide (10Panx1), and genetic deletion of Panx1 specifically in smooth muscle attenuated HPV in isolated perfused mouse lungs. In pulmonary artery smooth muscle cells (PASMCs), both spironolactone and 10Panx1 attenuated the increase in intracellular Ca2+ concentration ([Ca2+]i) in response to hypoxia. Yet, genetic deletion of Panx1 in either endothelial or smooth muscle cells did not prevent the development of PH in mice. Unexpectedly, ATP release in response to hypoxia was not detectable in PASMC, and inhibition of purinergic receptors or ATP degradation by ATPase failed to attenuate HPV. Rather, transient receptor potential vanilloid 4 (TRPV4) antagonism and Panx1 inhibition inhibited the hypoxia-induced [Ca2+]i increase in PASMC in an additive manner, suggesting that Panx1 regulates [Ca2+]i independently of the ATP-P2Y-TRPV4 pathway. In line with this notion, Panx1 overexpression increased the [Ca2+]i response to hypoxia in HeLa cells.ConclusionIn the present study, we identify Panx1 as novel regulator of HPV. Yet, the role of Panx1 in HPV was not attributable to ATP release and downstream signalling via P2Y receptors or TRPV4 activation, but relates to a role of Panx1 as direct or indirect modulator of the PASMC Ca2+ response to hypoxia. Panx1 did not affect the development of chronic hypoxic PH.

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CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction.

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CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction.

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