ALK1 and Endoglin regulation of EphrinB2 and sprout formation; Potential relevance to HHT

ALK1 and endoglin are an endothelial specific type I receptor of TGFβ receptors family whose mutations are responsible of Hereditary hemorrhagic telangiectasia (HHT). The notch pathway also works to pattern and stabilize the vasculature, and does so in conjunction with other angiogenic pathways including TGFβ/BMP. Arterial‐venous (AV) cell fate is determined before blood circulation starts, and pathways upstream of the arterial specific marker EphrinB2, and its receptor EphB4, a venous‐specific marker, are involved in this process including notch and TGFβ/BMP. In order to study crosstalk between ALK1/endoglin and notch and its functional significance, we investigated the role of these genes in the expression of EphrinB2 and EC sprout formation. We show that siRNA‐mediated knock down of ALK1 or endoglin suppressed EphrinB2 expression, and induced EC sprout formation in an in vitro angiogenesis assay. Knock down of EphrinB2 also resulted in increased sprouting. Addition of the ALK1 ligand BMP9 induced Ephrin B2 and also blocked sprouting. Finally, the loss of EphrinB2 expression in the absence of ALK1 could be overcome by activation of the notch pathway. These data support the concept of functional interaction between Notch signaling and BMP/ALK1 signaling in the regulation of EphrinB2 expression and endothelial sprouting. This work was supported by the HHT Foundation.