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

Ana Angulo-Urarte, Pedro Casado, Sandra D. Castillo, Piotr Kobialka, Maria Paraskevi Kotini, Ana M. Figueiredo, Pau Castel, Vinothini Rajeeve, Maria Milà-Guasch, Jaime Millan, Cora Wiesner, Helena Serra, Laia Muixi, Oriol Casanovas, Francesc Viñals, Markus Affolter, Holger Gerhardt, Stephan Huveneers, Heinz-Georg Belting, Pedro R. Cutillas and Mariona Graupera ()
Additional contact information
Ana Angulo-Urarte: Institut d´Investigació Biomèdica de Bellvitge (IDIBELL)
Pedro Casado: Queen Mary University of London
Sandra D. Castillo: Institut d´Investigació Biomèdica de Bellvitge (IDIBELL)
Piotr Kobialka: Institut d´Investigació Biomèdica de Bellvitge (IDIBELL)
Maria Paraskevi Kotini: Biozentrum der Universität Basel
Ana M. Figueiredo: Institut d´Investigació Biomèdica de Bellvitge (IDIBELL)
Pau Castel: University of California-San Francisco
Vinothini Rajeeve: Queen Mary University of London
Maria Milà-Guasch: Institut d´Investigació Biomèdica de Bellvitge (IDIBELL)
Jaime Millan: CSIC-UAM
Cora Wiesner: Biozentrum der Universität Basel
Helena Serra: Institut d´Investigació Biomèdica de Bellvitge (IDIBELL)
Laia Muixi: Institut d´Investigació Biomèdica de Bellvitge (IDIBELL)
Oriol Casanovas: IDIBELL
Francesc Viñals: IDIBELL
Markus Affolter: Biozentrum der Universität Basel
Holger Gerhardt: Max-Delbrueck Center for Molecular Medicine (MDC)
Stephan Huveneers: Amsterdam Cardiovascular Sciences
Heinz-Georg Belting: Biozentrum der Universität Basel
Pedro R. Cutillas: Queen Mary University of London
Mariona Graupera: Institut d´Investigació Biomèdica de Bellvitge (IDIBELL)

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07172-3

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