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Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility
Angiogenesis is a dynamic process relying on endothelial cell rearrangements within vascular tubes, yet the underlying mechanisms and functional relevance are poorly understood. Here we show that PI3Kα regulates endothelial cell rearrangements using a combination of a PI3Kα-selective inhibitor and e...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240100/ https://www.ncbi.nlm.nih.gov/pubmed/30446640 http://dx.doi.org/10.1038/s41467-018-07172-3 |
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author | Angulo-Urarte, Ana Casado, Pedro Castillo, Sandra D. Kobialka, Piotr Kotini, Maria Paraskevi Figueiredo, Ana M. Castel, Pau Rajeeve, Vinothini Milà-Guasch, Maria Millan, Jaime Wiesner, Cora Serra, Helena Muixi, Laia Casanovas, Oriol Viñals, Francesc Affolter, Markus Gerhardt, Holger Huveneers, Stephan Belting, Heinz-Georg Cutillas, Pedro R. Graupera, Mariona |
author_facet | Angulo-Urarte, Ana Casado, Pedro Castillo, Sandra D. Kobialka, Piotr Kotini, Maria Paraskevi Figueiredo, Ana M. Castel, Pau Rajeeve, Vinothini Milà-Guasch, Maria Millan, Jaime Wiesner, Cora Serra, Helena Muixi, Laia Casanovas, Oriol Viñals, Francesc Affolter, Markus Gerhardt, Holger Huveneers, Stephan Belting, Heinz-Georg Cutillas, Pedro R. Graupera, Mariona |
author_sort | Angulo-Urarte, Ana |
collection | PubMed |
description | Angiogenesis is a dynamic process relying on endothelial cell rearrangements within vascular tubes, yet the underlying mechanisms and functional relevance are poorly understood. Here we show that PI3Kα regulates endothelial cell rearrangements using a combination of a PI3Kα-selective inhibitor and endothelial-specific genetic deletion to abrogate PI3Kα activity during vessel development. Quantitative phosphoproteomics together with detailed cell biology analyses in vivo and in vitro reveal that PI3K signalling prevents NUAK1-dependent phosphorylation of the myosin phosphatase targeting-1 (MYPT1) protein, thereby allowing myosin light chain phosphatase (MLCP) activity and ultimately downregulating actomyosin contractility. Decreased PI3K activity enhances actomyosin contractility and impairs junctional remodelling and stabilization. This leads to overstretched endothelial cells that fail to anastomose properly and form aberrant superimposed layers within the vasculature. Our findings define the PI3K/NUAK1/MYPT1/MLCP axis as a critical pathway to regulate actomyosin contractility in endothelial cells, supporting vascular patterning and expansion through the control of cell rearrangement. |
format | Online Article Text |
id | pubmed-6240100 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-62401002018-11-19 Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility Angulo-Urarte, Ana Casado, Pedro Castillo, Sandra D. Kobialka, Piotr Kotini, Maria Paraskevi Figueiredo, Ana M. Castel, Pau Rajeeve, Vinothini Milà-Guasch, Maria Millan, Jaime Wiesner, Cora Serra, Helena Muixi, Laia Casanovas, Oriol Viñals, Francesc Affolter, Markus Gerhardt, Holger Huveneers, Stephan Belting, Heinz-Georg Cutillas, Pedro R. Graupera, Mariona Nat Commun Article Angiogenesis is a dynamic process relying on endothelial cell rearrangements within vascular tubes, yet the underlying mechanisms and functional relevance are poorly understood. Here we show that PI3Kα regulates endothelial cell rearrangements using a combination of a PI3Kα-selective inhibitor and endothelial-specific genetic deletion to abrogate PI3Kα activity during vessel development. Quantitative phosphoproteomics together with detailed cell biology analyses in vivo and in vitro reveal that PI3K signalling prevents NUAK1-dependent phosphorylation of the myosin phosphatase targeting-1 (MYPT1) protein, thereby allowing myosin light chain phosphatase (MLCP) activity and ultimately downregulating actomyosin contractility. Decreased PI3K activity enhances actomyosin contractility and impairs junctional remodelling and stabilization. This leads to overstretched endothelial cells that fail to anastomose properly and form aberrant superimposed layers within the vasculature. Our findings define the PI3K/NUAK1/MYPT1/MLCP axis as a critical pathway to regulate actomyosin contractility in endothelial cells, supporting vascular patterning and expansion through the control of cell rearrangement. Nature Publishing Group UK 2018-11-16 /pmc/articles/PMC6240100/ /pubmed/30446640 http://dx.doi.org/10.1038/s41467-018-07172-3 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Angulo-Urarte, Ana Casado, Pedro Castillo, Sandra D. Kobialka, Piotr Kotini, Maria Paraskevi Figueiredo, Ana M. Castel, Pau Rajeeve, Vinothini Milà-Guasch, Maria Millan, Jaime Wiesner, Cora Serra, Helena Muixi, Laia Casanovas, Oriol Viñals, Francesc Affolter, Markus Gerhardt, Holger Huveneers, Stephan Belting, Heinz-Georg Cutillas, Pedro R. Graupera, Mariona Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility |
title | Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility |
title_full | Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility |
title_fullStr | Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility |
title_full_unstemmed | Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility |
title_short | Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility |
title_sort | endothelial cell rearrangements during vascular patterning require pi3-kinase-mediated inhibition of actomyosin contractility |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240100/ https://www.ncbi.nlm.nih.gov/pubmed/30446640 http://dx.doi.org/10.1038/s41467-018-07172-3 |
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