Abstract
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.
MeSH terms
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Animals
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Arteriovenous Malformations / genetics
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Arteriovenous Malformations / metabolism
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Arteriovenous Malformations / pathology
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Arteriovenous Malformations / prevention & control*
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Cell Lineage
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Cell Proliferation
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Cells, Cultured
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Disease Models, Animal
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Endoglin / deficiency
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Endoglin / genetics
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Endoglin / metabolism*
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Endothelial Cells / metabolism*
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Endothelial Cells / pathology
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Genetic Predisposition to Disease
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Humans
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Kinetics
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Mice, Knockout
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Neovascularization, Pathologic*
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Neovascularization, Physiologic*
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Phenotype
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Phosphatidylinositol 3-Kinase / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Signal Transduction*
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Stress, Mechanical
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Telangiectasia, Hereditary Hemorrhagic / genetics
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Telangiectasia, Hereditary Hemorrhagic / metabolism
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Telangiectasia, Hereditary Hemorrhagic / pathology
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Telangiectasia, Hereditary Hemorrhagic / prevention & control*
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Tissue Culture Techniques
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Transfection
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism*
Substances
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Endoglin
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Eng protein, mouse
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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Phosphatidylinositol 3-Kinase
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Kdr protein, mouse
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Vascular Endothelial Growth Factor Receptor-2
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Proto-Oncogene Proteins c-akt