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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Detalhes bibliográficos
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
Descrição
Resumo: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.

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