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

Kishor K Sivaraj,Susanne Adams,Katsuhiro Kato,Hyun-Woo Jeong,Silke Schröder,Gou Young Koh,Backialakshmi Dharmalingam,Ralf H Adams,Vishal Mohanakrishnan

doi:10.7554/elife.50770

Abstract

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.

Highlights

The skeletal system is surprisingly dynamic and undergoes lifelong remodeling even after the completion of developmental growth
We show that Yes-associated protein 1 (Yap1)/Taz negatively regulate the activity of the hypoxia-inducible factor (HIF) pathway and thereby limit the expression of endothelial genes associated with vessel growth
It was already shown that the loss of Yap1/Taz in endothelial cells (ECs) impairs endothelial proliferation and sprouting in the embryo and postnatal retina, whereas genetic gain-of-function experiments lead to endothelial hypersprouting and vascular hyperplasia (Kim et al, 2017; Neto et al, 2018; Sakabe et al, 2017; Wang et al, 2017)

Summary

Introduction

The skeletal system is surprisingly dynamic and undergoes lifelong remodeling even after the completion of developmental growth. Endochondral ossification and, in particular, the formation of ossification centers in the mouse embryo requires the ingrowth of blood vessels into aggregates of hypertrophic chondrocytes that express pro-angiogenic signals such as vascular endothelial growth factor A (VEGF-A) (Eshkar-Oren et al, 2009; Maes et al, 2010). The invasion of blood vessels facilitates the entry of osteoblast precursors into fractured bone and, angiogenesis is essential for bone repair and regeneration (Maes et al, 2010; Stegen et al, 2015). Columnar vessels in the metaphysis and the capillaries of the endosteum, a connective tissue layer lining the inner surface of compact bone, are associated with osteoprogenitor

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