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Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Forskargrupp Taija Mäkinen)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.ORCID iD: 0000-0002-9050-0978
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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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, no 1, article id 1296Article in journal (Refereed) Published
Abstract [en]

Incomplete delivery to the target cells is an obstacle for successful gene therapy approaches. Here we show unexpected effects of incomplete targeting, by demonstrating how heterogeneous inhibition of a growth promoting signaling pathway promotes tissue hyperplasia. We studied the function of the lymphangiogenic VEGFR3 receptor during embryonic and post-natal development. Inducible genetic deletion of Vegfr3 in lymphatic endothelial cells (LECs) leads to selection of non-targeted VEGFR3+cells at vessel tips, indicating an indispensable cell-autonomous function in migrating tip cells. Although Vegfr3 deletion results in lymphatic hypoplasia in mouse embryos, incomplete deletion during post-natal development instead causes excessive lymphangiogenesis. Analysis of mosaically targeted endothelium shows that VEGFR3-LECs non-cell-autonomously drive abnormal vessel anastomosis and hyperplasia by inducing proliferation of non-targeted VEGFR3+LECs through cell-contact-dependent reduction of Notch signaling. Heterogeneity in VEGFR3 levels thus drives vessel hyperplasia, which has implications for the understanding of mechanisms of developmental and pathological tissue growth.

Place, publisher, year, edition, pages
2018. Vol. 9, no 1, article id 1296
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-348896DOI: 10.1038/s41467-018-03692-0ISI: 000429003400001PubMedID: 29615616OAI: oai:DiVA.org:uu-348896DiVA, id: diva2:1198820
Funder
Swedish Research Council, 542-2014-3535EU, European Research Council, ERC-2014-CoG-646849Knut and Alice Wallenberg Foundation, 2015.0030Stiftelsen G A Johanssons Minnesfond
Available from: 2018-04-18 Created: 2018-04-18 Last updated: 2018-06-13Bibliographically approved

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Zhang, YanUlvmar, Maria H.Stanczuk, LukasMartinez-Corral, InesFrye, MaikeMäkinen, Taija

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