YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation

Abstract

Angiogenesis is a multistep process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches in response to growth stimuli. Major intracellular signaling pathways that regulate angiogenesis have been well elucidated, but key transcriptional regulators that mediate these signaling pathways and control EC behaviors are only beginning to be understood. Here, we show that YAP/TAZ, a transcriptional coactivator that acts as an end effector of Hippo signaling, is critical for sprouting angiogenesis and vascular barrier formation and maturation. In mice, endothelial-specific deletion of Yap/Taz led to blunted-end, aneurysm-like tip ECs with fewer and dysmorphic filopodia at the vascular front, a hyper-pruned vascular network, reduced and disarranged distributions of tight and adherens junction proteins, disrupted barrier integrity, subsequent hemorrhage in growing retina and brain vessels, and reduced pathological choroidal neovascularization. Mechanistically, YAP/TAZ activates actin cytoskeleton remodeling, an important component of filopodia formation and junction assembly. Moreover, YAP/TAZ coordinates EC proliferation and metabolic activity by upregulating MYC signaling. Overall, these results show that YAP/TAZ plays multifaceted roles for EC behaviors, proliferation, junction assembly, and metabolism in sprouting angiogenesis and barrier formation and maturation and could be a potential therapeutic target for treating neovascular diseases.

Retinal blood vessel‐origin yes‐associated protein (YAP) governs astrocytic maturation via leukaemia inhibitory factor (LIF)

“…Tek-Cre mice have been widely used for retinal vascular research. [32][33][34] Consistent with a previous study, 35 the ECs in the tip of the vascular front region of YAP cKO mice exhibited a blunted end with fewer dysmorphic filopodia ( Figure 2B). Since a previous study showed that TAZ cKO mice appeared normal and had no obvious vascular phenotype, the current study examined YAP cKO mice, which exhibit a gene dose-dependent dysfunctional vascular phenotype.…”

Keratin 14-dependent disulfides regulate epidermal homeostasis and barrier function via 14-3-3σ and YAP1

“…Third, the Krt10 null mouse exhibits an intriguing phenotype of hyperproliferation, faster keratinocyte transit time, and impaired differentiation in the epidermis which, molecularly, correlates with a marked upregulation of 14-3-3sigma and c-Myc (Reichelt and Magin 2002;Reichelt et al 2004). MYC has since then been shown to be a bona fide YAP1 target gene (Schutte et al 2014;Kim et al 2017;Cai et al 2018). Possibly, therefore, K10 could extend the role of K14 as keratinocytes progress through terminal differentiation (Fig.…”

Yaphaploinsufficiency leads to Müller cell dysfunction and late-onset cone dystrophy

“…We observed a reduction of intermediate vascular plexus without any blood leakage in 12-month-old Yap +/retinal flat-mounts compared to controls (Supplementary Figure S13B and Supplementary Figure S14). Although recent studies have shown that YAP/TAZ are involved in vascular retinal development (Kim et al, 2017), no differences could be observed after labelling the three capillary plexi between 8-month-old Yap +/mice and controls (Supplementary Figure S13B). Such observation ruled out significant developmental defects of vascular networks.…”