Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling

Loss-of-function (LOF) mutations in the endothelial cell (EC) enriched gene endoglin (ENG) causes the human disease hereditary haemorrhagic telangiectasia-1, characterized by vascular malformations promoted by vascular endothelial growth factor A (VEGFA). How ENG deficiency alters EC behaviour to trigger these anomalies is not understood. Mosaic ENG deletion in the postnatal mouse rendered Eng LOF ECs insensitive to flow-mediated venous to arterial migration. Eng LOF ECs retained within arterioles acquired venous characteristics and secondary ENG-independent proliferation resulting in arterio-venous malformation (AVM). Analysis following simultaneous Eng LOF and overexpression (OE) revealed that ENG OE ECs dominate tip cell positions and home preferentially to arteries. ENG knock-down altered VEGFA-mediated VEGFR2 kinetics and promoted AKT signalling. Blockage of PI3K/AKT partly normalised flow-directed migration of ENG LOF ECs in vitro and reduced the severity of AVM in vivo. This demonstrates the requirement of ENG in flow-mediated migration and modulation of VEGFR2 signalling in vascular patterning.