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Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling
Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
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2017 (English)In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 19, no 6, 639-652 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 19, no 6, 639-652 p.
National Category
Cell and Molecular Biology
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URN: urn:nbn:se:uu:diva-330738DOI: 10.1038/ncb3534ISI: 000402525200012PubMedID: 28530660OAI: oai:DiVA.org:uu-330738DiVA: diva2:1148416
Funder
Swedish Research CouncilSwedish Cancer SocietyMagnus Bergvall FoundationKnut and Alice Wallenberg FoundationEU, European Research Council
Available from: 2017-10-11 Created: 2017-10-11 Last updated: 2017-10-11Bibliographically approved

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Betsholtz, Christer

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