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The endothelial adaptor molecule TSAd is required for VEGF-induced angiogenic sprouting through junctional c-Src activation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Kyorin Univ, Sch Med, Dept Pediat, 6-20-2 Shinkawa, Mitaka, Tokyo 1818611, Japan..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
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2016 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 9, no 437, ra72Article in journal (Refereed) Published
Abstract [en]

Activation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by VEGF binding is critical for vascular morphogenesis. In addition, VEGF disrupts the endothelial barrier by triggering the phosphorylation and turnover of the junctional molecule VE-cadherin, a process mediated by the VEGFR2 downstream effectors T cell-specific adaptor (TSAd) and the tyrosine kinase c-Src. We investigated whether the VEGFR2-TSAd-c-Src pathway was required for angiogenic sprouting. Indeed, Tsad-deficient embryoid bodies failed to sprout in response to VEGF. Tsad-deficient mice displayed impaired angiogenesis specifically during tracheal vessel development, but not during retinal vasculogenesis, and in VEGF-loaded Matrigel plugs, but not in those loaded with FGF. The SH2 and proline-rich domains of TSAd bridged VEGFR2 and c-Src, and this bridging was critical for the localization of activated c-Src to endothelial junctions and elongation of the growing sprout, but not for selection of the tip cell. These results revealed that vascular sprouting and permeability are both controlled through the VEGFR2-TSAd-c-Src signaling pathway in a subset of tissues, which may be useful in developing strategies to control tissue-specific pathological angiogenesis.

Place, publisher, year, edition, pages
2016. Vol. 9, no 437, ra72
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-302704DOI: 10.1126/scisignal.aad9256ISI: 000380779000002PubMedID: 27436360OAI: oai:DiVA.org:uu-302704DiVA: diva2:967386
Funder
Wenner-Gren FoundationsSwedish Cancer Society, CAN 2013/661Swedish Research Council, 2015-03275Knut and Alice Wallenberg Foundation
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2016-09-08 Created: 2016-09-08 Last updated: 2016-09-08Bibliographically approved

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Gordon, Emma J.Weström, SimonePadhan, NarendraHe, LiqunDejana, ElisabettaBentley, KatieClaesson-Welsh, Lena
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Vascular BiologyDepartment of Immunology, Genetics and Pathology
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