Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms

Yan Zhang, Maria H. Ulvmar, Lukas Stanczuk, Ines Martinez-Corral, Maike Frye, Kari Alitalo and Taija Mäkinen ()
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Yan Zhang: Uppsala University
Maria H. Ulvmar: Uppsala University
Lukas Stanczuk: Uppsala University
Ines Martinez-Corral: Uppsala University
Maike Frye: Uppsala University
Kari Alitalo: University of Helsinki
Taija Mäkinen: Uppsala University

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03692-0

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DOI: 10.1038/s41467-018-03692-0

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