BMP6: a growth factor mediating Hippo signaling pathway and vessel formation

Emerging knowledge supports the role of bone morphogenetic proteins (BMPs) in vascular homeostasis and angiogenesis. Dysfunctional BMP signaling is involved in various vascular disorders, such as hereditary hemorrhagic telangiectasia, cerebral cavernous malformation and atherosclerosis. Synergistic effect of VEGF‐A and BMPs on vasculature have been previously detected in bone formation but their role in angiogenesis, particularly crosstalk with VEGFR2 signaling has remained elusive. Recently, BMPR pathway was linked for the first time to dysfunctional Hippo‐signaling, though the exact extracellular ligands, interaction mechanisms and end‐responses remained unknown. Hippo pathway has previously been shown to regulate multiple cellular functions such as cell proliferation, survival, differentiation, migration and apoptosis. Dysregulation of Hippo signaling pathway has also been linked to cancer metastasis, and to epithelioid hemangioendothelioma. We studied here the role of BMPs in angiogenesis and VEGF‐induced endothelial cell response. We identified BMP6 as the first BMP family member directly regulating both Hippo signaling pathway, by inducing nuclear localization of TAZ, and vessel formation. Thus, BMP6 may serve as a potential target for anti‐angiogenic therapy.