YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

Significance

New blood vessel formation is a physiological process seen in development, as well as in wound healing and tumorigenesis. Although the process of blood vasculature formation has been well documented, little is known about the molecular mechanisms that regulate endothelial migration during vascular network formation. In this study, we identified a critical role for Hippo effectors YAP and TAZ in the regulation of vascular network remodeling through controlling endothelial cell (EC) proliferation, filopodia formation, and cell migration. We found a striking cytoplasmic function of YAP in the regulation of EC migration through controlling the Rho family GTPase CDC42 activity. These findings identify a previously unrecognized YAP/TAZ function involved in the vascular network remodeling during angiogenesis.

Abstract

Angiogenesis and vascular remodeling are essential for the establishment of vascular networks during organogenesis. Here we show that the Hippo signaling pathway effectors YAP and TAZ are required, in a gene dosage-dependent manner, for the proliferation and migration of vascular endothelial cells (ECs) during retinal angiogenesis. Intriguingly, nuclear translocation of YAP and TAZ induced by Lats1/ 2-deletion blocked endothelial migration and phenocopied Yap/Taz-deficient mutants. Furthermore, overexpression of a cytoplasmic form of YAP (YAPS127D) partially rescued the migration defects caused by loss of YAP and TAZ function. Finally, we found that cytoplasmic YAP positively regulated the activity of the small GTPase CDC42, deletion of which caused severe defects in endothelial migration. These findings uncover a previously unrecognized role of cytoplasmic YAP/TAZ in promoting cell migration by activating CDC42 and provide insight into how Hippo signaling in ECs regulates angiogenesis.