YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

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.A ngiogenesis is a process of growth and remodeling in vascular networks that is essential for normal development. In adulthood, angiogenesis is activated as a reparative process, for example, during wound healing (1, 2). Aberrantly regulated angiogenesis can also be a component of disease (3) and can play a key role in tumor growth and metastasis (4), inflammatory diseases (5), diabetic retinopathy, and retinopathy of prematurity (6).Retinal angiogenesis in mice begins at postnatal day 0 (P0). The retinal vasculature initiates its expansion from the optic nerve head and migrates outwards along a preexisting network of astrocytes (7,8). This results in the formation of the superficial vascular plexus within the retinal ganglion cell layer during the first 8 d (9, 10). Endothelial cells (ECs) then migrate along nerve fibers to establish deep and intermediate vascular layers (9,11). Cell proliferation and migration are essential for angiogenesis and these cell responses are regulated by many different signaling pathways, including the VEGF, Notch, Wnt, FGF, BMP, and integrin signaling responses (9, 12-16). VEGFA and CDC42 are known to regulate extension of the angiogenic front and filopodia formation in angiogenic tip cells (2,17,18).The Hippo signaling pathway is an evolutionarily conserved, pivotal regulator of cell proliferation and organogenesis. YAP and TAZ are key components of the Hippo signaling pathway and function as transcription cofactors that regulate downstream gene expression via association with DNA binding proteins such as 20). Loss of Hippo signaling can drive the expression of genes that regulate cell proliferation and survival (diap1, bantam, cyclin E, and E2F1), the Hippo pathway (Kibra, Crb, and Fj), and cell-cell interaction (E-Cadherin, Serrate, Wingless, and Vein) (20). The activity of YAP and TAZ is regulated by the LATS1 and LATS2 kinases. These kinases phosphorylate YAP and TAZ, thus preventing their nuclear translocation and regulating transcriptional activity. Although the function of YAP and TAZ in the ...

Mechanobiological Conditioning of Mesenchymal Stem Cells Enhances Therapeutic Angiogenesis by Inducing a Hybrid Pericyte-Endothelial Phenotype

“…However, these pathways have also been linked to angiogenesis and pericyte function. Signaling through Yap/Taz is enhanced in the tip cells of capillaries during angiogenesis and vascular development [54][55][56] . In addition, pericyte-specific knockout of Yap and Taz disrupts their coordination of alveologenesis by reducing their production of HGF 57 .…”

Retinoic acid signaling in heart development

“…The Hippo signaling pathway is thought to control organ size by regulating cellular expansion, reduction, and migration (Sakabe et al, 2017). Hippo pathway kinases, Lats1/2, which phosphorylate Yap transcriptional co-factor to inhibit its nuclear translocation, are expressed in the epicardium/hepatic mesoderm.…”

Fat1 regulates astrocyte maturation and angiogenesis in the retina

“…As ECs migrate radially on the astrocytic layer, allowing the vascular network to expand, the 31 rise in oxygen level resulting from blood perfusion in newly formed vessels locally promotes the 32 conversion of immature astrocytes into mature astrocytes, characterized by increased 33 expression of the astrocyte marker glial fibrillary acidic protein (GFAP) and reduced VEGF 34 expression levels proximal to the vascular front (West et al, 2005). This oxygen-mediated 35 silencing of VEGF expression in astrocytes in contact with ECs (proximal to the vascular front), is 36 opposed to the high VEGF levels induced by hypoxia in the EC-free distal region ahead of the 37 vascular front (Duan et al, 2017;Duan et al, 2014;Rattner et al, 2019;Stone et al, 1995). This 38 dual regulation establishes a gradient of VEGF (high in immature astrocytes, low in mature 39 astrocytes), determining the outward direction polarity of EC migration (West et al, 2005).…”