Characterizing the interaction between Hippo/YAP signaling and FOXO1 during sprouting angiogenesis

Abstract

Angiogenesis is a multi-step process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches. Major intracellular signaling pathways regulating angiogenesis have been well elucidated, but key transcriptional regulators that mediate the signaling pathways in response to extracellular stimuli and control EC behaviors are only beginning to be understood. Here, I show that LATS1/2-YAP/TAZ and MST1-FOXO1 cascades respond to extracellular angiogenic stimuli and facilitate vascular sprout formation. Mechanistically, in response to vascular endothelial growth factor (VEGF), YAP/TAZ activate actin cytoskeleton remodeling, an important component of filopodia formation. On the other hand, although MST1 is an upstream regulator of Hippo/YAP signaling, it is not activated by VEGF, rather phosphorylated by hypoxia. In addition, it does not rely on the Hippo/YAP signaling in ECs, rather promotes nuclear import of FOXO1 for augmenting transcriptional activity related to the polarity/migration-associated genes. Taken together, my data delineates independent couplings between extracellular stimuli and transcriptional regulators, VEGF-LATS1/2-YAP/TAZ and hypoxia-MST1-FOXO1, and illuminates their promoting roles in sprouting angiogenesis.