Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling
Copyright policy )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) cause 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 arteriovenous 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 knockdown altered VEGFA-mediated VEGFR2 kinetics and promoted AKT signalling. Blockage of PI(3)K/AKT partly normalized 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.
- Uppsala University Sweden
- Karolinska Institute Sweden
- Integrated Cardio Metabolic Centre Sweden
- Newcastle University United Kingdom
- Stockholm University Sweden
Mice, Knockout, Neovascularization, Pathologic, Endoglin, Endothelial Cells, Neovascularization, Physiologic, Article, Arteriovenous Malformations, Disease Models, Animal, Kinetics, Phenotype, Animals, Humans, Cell Lineage, Genetic Predisposition to Disease, RNA Interference, Stress, Mechanical, Phosphatidylinositol 3-Kinase, Proto-Oncogene Proteins c-akt, Cells, Cultured, Cell Proliferation, Signal Transduction
Mice, Knockout, Neovascularization, Pathologic, Endoglin, Endothelial Cells, Neovascularization, Physiologic, Article, Arteriovenous Malformations, Disease Models, Animal, Kinetics, Phenotype, Animals, Humans, Cell Lineage, Genetic Predisposition to Disease, RNA Interference, Stress, Mechanical, Phosphatidylinositol 3-Kinase, Proto-Oncogene Proteins c-akt, Cells, Cultured, Cell Proliferation, Signal Transduction
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