Cell rearrangement during angiogenesis requires suppression of actomyosin at cell-cell contacts via PI3-kinase.

ABSTRACT: Sprouting angiogenesis is a highly dynamic process which relies on the continuous interchange of endothelial cell relative position within the vascular sprout, a process mediated by cell rearrangements. Here we take advantage of a previous identified role of p110a/PI3K regulating endothelial cell motility to address how cell rearrangement and interaction regulate vessel growth. By using advanced fluorescent zebrafish models and a tamoxifen-inducible endothelial-specific gene targeting in the postnatal mouse retina, we demonstrate that inactivation of the p110a isoform of PI3K in endothelial cells is a good model to study cell shuffling in the growing vasculature. We identify that a failure of endothelial cells to rearrange results in cell elongation and inability to stabilize new contacts upon anastomosis. Instead of rearrange, blockade of p110 signaling drive these cells to grow in a three dimension fashion by sending multiple protrusions which lack lumen and fail to stabilize upon anastomosis. Through a combination of in vivo and in vitro approaches together with a global phosphoproteomic screen, we discover that p110a signaling stimulates cell rearrangements by suppressing actomyosin contractility in a myosin light chain phosphatase (MLCP) dependent manner. Together, our findings highlight the importance of cell rearrangement orchestrating several steps within the angiogenic program and uncover a critical role of the p110a/MLCP axis to suppress actomyosin contractility.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Primary Cell, Epithelial Cell

SUBMITTER: Pedro Casado-Izquierdo  

LAB HEAD: Pedro R. Cutillas

PROVIDER: PXD007060 | Pride | 2018-10-02

REPOSITORIES: Pride