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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Angulo-Urarte A,Casado P,Castillo SD,Kobialka P,Kotini MP,Figueiredo AM,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 HG,Cutillas

doi

10.1038/s41467-018-07172-3

subject

Has Abstract

pub_date

2018-11-16 00:00:00

pages

4826

issue

1

issn

2041-1723

pii

10.1038/s41467-018-07172-3

journal_volume

9

pub_type

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