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...

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Autores: Angulo Urarte, Ana, Casado, Pedro, Castillo, Sandra D., Kobialka, Piotr, Kotini, Maria Paraskevi, Figueiredo, Ana Raquel Martins, Castel Morales, Pau, Rajeeve, Vinothini, Milà Guasch, Maria, Millán, Jaime, Wiesner, Cora, Serra, Helena, Muixi, Laura, Casanovas i Casanovas, Oriol, Viñals Canals, Francesc, Affolter, Markus, Gerhardt, Holger, Huveneers, Stephan, Belting, Heinz-Georg, Cutillas, Pedro R., Graupera i Garcia-Milà, Mariona
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2018
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositório:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/133450
Acesso em linha:https://hdl.handle.net/2445/133450
Access Level:Acceso aberto
Palavra-chave:Proteïnes quinases
Angiogènesi
Regulació genètica
Expressió gènica
Protein kinases
Neovascularization
Genetic regulation
Gene expression
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repository_id_str
spelling Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractilityAngulo Urarte, AnaCasado, PedroCastillo, Sandra D.Kobialka, PiotrKotini, Maria ParaskeviFigueiredo, Ana Raquel MartinsCastel Morales, PauRajeeve, VinothiniMilà Guasch, MariaMillán, JaimeWiesner, CoraSerra, HelenaMuixi, LauraCasanovas i Casanovas, OriolViñals Canals, FrancescAffolter, MarkusGerhardt, HolgerHuveneers, StephanBelting, Heinz-GeorgCutillas, Pedro R.Graupera i Garcia-Milà, MarionaProteïnes quinasesAngiogènesiRegulació genèticaExpressió gènicaProtein kinasesNeovascularizationGenetic regulationGene expressionAngiogenesis 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 Group2019201920182019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion16 p.application/pdfhttps://hdl.handle.net/2445/133450Articles publicats en revistes (Ciències Fisiològiques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1038/s41467-018-07172-3Nature Communications, 2018, vol. 9, num. 1, p. 4826https://doi.org/10.1038/s41467-018-07172-3info:eu-repo/grantAgreement/EC/H2020/675392info:eu-repo/grantAgreement/EC/H2020/749731cc-by (c) Angulo Urarte, Ana et al., 2018http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1334502026-05-29T05:05:01Z
dc.title.none.fl_str_mv 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
spellingShingle Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility
Angulo Urarte, Ana
Proteïnes quinases
Angiogènesi
Regulació genètica
Expressió gènica
Protein kinases
Neovascularization
Genetic regulation
Gene expression
title_short 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_sort Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility
dc.creator.none.fl_str_mv Angulo Urarte, Ana
Casado, Pedro
Castillo, Sandra D.
Kobialka, Piotr
Kotini, Maria Paraskevi
Figueiredo, Ana Raquel Martins
Castel Morales, Pau
Rajeeve, Vinothini
Milà Guasch, Maria
Millán, Jaime
Wiesner, Cora
Serra, Helena
Muixi, Laura
Casanovas i Casanovas, Oriol
Viñals Canals, Francesc
Affolter, Markus
Gerhardt, Holger
Huveneers, Stephan
Belting, Heinz-Georg
Cutillas, Pedro R.
Graupera i Garcia-Milà, Mariona
author Angulo Urarte, Ana
author_facet Angulo Urarte, Ana
Casado, Pedro
Castillo, Sandra D.
Kobialka, Piotr
Kotini, Maria Paraskevi
Figueiredo, Ana Raquel Martins
Castel Morales, Pau
Rajeeve, Vinothini
Milà Guasch, Maria
Millán, Jaime
Wiesner, Cora
Serra, Helena
Muixi, Laura
Casanovas i Casanovas, Oriol
Viñals Canals, Francesc
Affolter, Markus
Gerhardt, Holger
Huveneers, Stephan
Belting, Heinz-Georg
Cutillas, Pedro R.
Graupera i Garcia-Milà, Mariona
author_role author
author2 Casado, Pedro
Castillo, Sandra D.
Kobialka, Piotr
Kotini, Maria Paraskevi
Figueiredo, Ana Raquel Martins
Castel Morales, Pau
Rajeeve, Vinothini
Milà Guasch, Maria
Millán, Jaime
Wiesner, Cora
Serra, Helena
Muixi, Laura
Casanovas i Casanovas, Oriol
Viñals Canals, Francesc
Affolter, Markus
Gerhardt, Holger
Huveneers, Stephan
Belting, Heinz-Georg
Cutillas, Pedro R.
Graupera i Garcia-Milà, Mariona
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Proteïnes quinases
Angiogènesi
Regulació genètica
Expressió gènica
Protein kinases
Neovascularization
Genetic regulation
Gene expression
topic Proteïnes quinases
Angiogènesi
Regulació genètica
Expressió gènica
Protein kinases
Neovascularization
Genetic regulation
Gene expression
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.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/133450
url https://hdl.handle.net/2445/133450
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41467-018-07172-3
Nature Communications, 2018, vol. 9, num. 1, p. 4826
https://doi.org/10.1038/s41467-018-07172-3
info:eu-repo/grantAgreement/EC/H2020/675392
info:eu-repo/grantAgreement/EC/H2020/749731
dc.rights.none.fl_str_mv cc-by (c) Angulo Urarte, Ana et al., 2018
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Angulo Urarte, Ana et al., 2018
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 16 p.
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869403539212599296
score 15,812455

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