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- Publisher Website: 10.1093/cvr/cvx076
- Scopus: eid_2-s2.0-85021780329
- PMID: 28430879
- WOS: WOS:000404612600010
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Article: Role of phosphatase and tensin homolog in hypoxic pulmonary vasoconstriction
Title | Role of phosphatase and tensin homolog in hypoxic pulmonary vasoconstriction |
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Authors | |
Keywords | Transient receptor potential canonical 6 (TRPC6) Rho kinase (ROCK) Hypoxia Phosphatase and tensin homolog (PTEN) Pulmonary artery smooth muscle cells (PASMC) |
Issue Date | 2017 |
Citation | Cardiovascular Research, 2017, v. 113, n. 8, p. 869-878 How to Cite? |
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 PTENTRPC6 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. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. |
Persistent Identifier | http://hdl.handle.net/10722/293023 |
ISSN | 2023 Impact Factor: 10.2 2023 SCImago Journal Rankings: 2.809 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Krauszman, Adrienn | - |
dc.contributor.author | Mak, Tak W. | - |
dc.contributor.author | Szaszi, Katalin | - |
dc.contributor.author | Kuebler, Wolfgang M. | - |
dc.date.accessioned | 2020-11-17T14:57:42Z | - |
dc.date.available | 2020-11-17T14:57:42Z | - |
dc.date.issued | 2017 | - |
dc.identifier.citation | Cardiovascular Research, 2017, v. 113, n. 8, p. 869-878 | - |
dc.identifier.issn | 0008-6363 | - |
dc.identifier.uri | http://hdl.handle.net/10722/293023 | - |
dc.description.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 PTENTRPC6 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. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. | - |
dc.language | eng | - |
dc.relation.ispartof | Cardiovascular Research | - |
dc.subject | Transient receptor potential canonical 6 (TRPC6) | - |
dc.subject | Rho kinase (ROCK) | - |
dc.subject | Hypoxia | - |
dc.subject | Phosphatase and tensin homolog (PTEN) | - |
dc.subject | Pulmonary artery smooth muscle cells (PASMC) | - |
dc.title | Role of phosphatase and tensin homolog in hypoxic pulmonary vasoconstriction | - |
dc.type | Article | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1093/cvr/cvx076 | - |
dc.identifier.pmid | 28430879 | - |
dc.identifier.pmcid | PMC5852630 | - |
dc.identifier.scopus | eid_2-s2.0-85021780329 | - |
dc.identifier.volume | 113 | - |
dc.identifier.issue | 8 | - |
dc.identifier.spage | 869 | - |
dc.identifier.epage | 878 | - |
dc.identifier.eissn | 1755-3245 | - |
dc.identifier.isi | WOS:000404612600010 | - |
dc.identifier.issnl | 0008-6363 | - |