Dataset Information

Role of phosphatase and tensin homolog in hypoxic pulmonary vasoconstriction.

ABSTRACT:

Aims

Hypoxic pulmonary vasoconstriction (HPV) redistributes blood flow from poorly ventilated to better aerated areas in the lung, thereby optimizing ventilation-perfusion ratio (V/Q). Pulmonary artery smooth muscle cell (PASMC) contraction in response to hypoxia is triggered by Ca2+ influx via transient receptor potential canonical 6 (TRPC6) cation channels that have translocated to caveolae in the plasma membrane. Since phosphatase and tensin homolog (PTEN) was suggested to regulate TRPC6 in endothelial cells, we aimed to define its role in the hypoxic response of PASMCs and as a putative mediator of HPV.

Methods and results

In isolated perfused mouse lungs, smooth muscle specific PTEN deficiency attenuated pulmonary vasoconstriction in response to hypoxia but not to angiotensin II (Ang II). Analogously, siRNA-mediated knock down of PTEN in human PASMC inhibited the hypoxia-induced increase in cytosolic Ca2+ concentration ([Ca2+]i). Co-immunoprecipitation and proximity ligation assays revealed increased interaction of PTEN with TRPC6 in human PASMC and murine lungs in response to hypoxia. In hypoxic PASMC, both PTEN and TRPC6 translocated to caveolae, and this response was blocked by pharmacological inhibition of Rho-associated protein kinase (ROCK) which in parallel prevented PTEN-TRPC6 interaction, hypoxia-induced [Ca2+]i increase, and HPV in PASMC and murine lungs, respectively.

Conclusion

Our data indicate a novel interplay between ROCK and [Ca2+]i signalling in HPV via PTEN, in that ROCK mediates interaction of PTEN and TRPC6 which then conjointly translocate to caveolae allowing for Ca2+ influx into and subsequent contraction of PASMC.

SUBMITTER: Krauszman A

PROVIDER: S-EPMC5852630 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

Role of phosphatase and tensin homolog in hypoxic pulmonary vasoconstriction.

Krauszman Adrienn A Mak Tak W TW Szaszi Katalin K Kuebler Wolfgang M WM

Cardiovascular research 20170701 8

<h4>Aims</h4>Hypoxic pulmonary vasoconstriction (HPV) redistributes blood flow from poorly ventilated to better aerated areas in the lung, thereby optimizing ventilation-perfusion ratio (V/Q). Pulmonary artery smooth muscle cell (PASMC) contraction in response to hypoxia is triggered by Ca2+ influx via transient receptor potential canonical 6 (TRPC6) cation channels that have translocated to caveolae in the plasma membrane. Since phosphatase and tensin homolog (PTEN) was suggested to regulate TR ...[more]

PMID: 28430879

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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.

Dataset Information

Role of phosphatase and tensin homolog in hypoxic pulmonary vasoconstriction.

Aims

Methods and results

Conclusion

Publications

Role of phosphatase and tensin homolog in hypoxic pulmonary vasoconstriction.

Similar Datasets

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