YAP1 and TAZ negatively control bone angiogenesis by limiting hypoxia-inducible factor signaling in endothelial cells

Blood vessels are integrated into different organ environments with distinct properties and physiology (Augustin and Koh, 2017). A striking example of organ-specific specialization is the bone vasculature where certain molecular signals yield the opposite effect as in other tissues (Glomski et al., 2011; Kusumbe et al., 2014; Ramasamy et al., 2014). Here, we show that the transcriptional coregulators Yap1 and Taz, components of the Hippo pathway, suppress vascular growth in the hypoxic microenvironment of bone, in contrast to their pro-angiogenic role in other organs. Likewise, the kinase Lats2, which limits Yap1/Taz activity, is essential for bone angiogenesis but dispensable in organs with lower levels of hypoxia. With mouse genetics, RNA sequencing, biochemistry, and cell culture experiments, we show that Yap1/Taz constrain hypoxia-inducible factor 1α (HIF1α) target gene expression in vivo and in vitro. We propose that crosstalk between Yap1/Taz and HIF1α controls angiogenesis depending on the level of tissue hypoxia, resulting in organ-specific biological responses.