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Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility

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Item Type:Article
Title:Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility
Creators Name:Angulo-Urarte, A., Casado, P., Castillo, S.D., Kobialka, P., Kotini, M.P., Figueiredo, A.M., Castel, P., Rajeeve, V., Milà-Guasch, M., Millan, J., Wiesner, C., Serra, H., Muixi, L., Casanovas, O., Viñals, F., Affolter, M., Gerhardt, H., Huveneers, S., Belting, H.G., Cutillas, P.R. and Graupera, M.
Abstract: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.
Keywords:Actomyosin, Body Patterning, Mammalian, Embryo, Nonmammalian, Embryo, Gene Expression Profiling, Developmental, Gene Expression Regulation, Human Umbilical Vein Endothelial Cells, Intercellular Junctions, Lung, Inbred C57BL, Mice, Transgenic, Mice, Myosin-Light-Chain Phosphatase, Physiologic, Neovascularization, Phosphatidylinositol 3-Kinases, Phosphoproteins, Protein Kinases, Repressor Proteins, Retina, Signal Transduction, Animals, Mice, Zebrafish
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:4826
Date:16 November 2018
Official Publication:https://doi.org/10.1038/s41467-018-07172-3
PubMed:View item in PubMed

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