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

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Zhang , Y , Ulvmar , M H , Stanczuk , L , Martinez-Corral , I , Frye , M , Alitalo , K & Mäkinen , T 2018 , ' Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms ' , Nature Communications , vol. 9 , 1296 . https://doi.org/10.1038/s41467-018-03692-0

Title: Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms
Author: Zhang, Yan; Ulvmar, Maria H.; Stanczuk, Lukas; Martinez-Corral, Ines; Frye, Maike; Alitalo, Kari; Mäkinen, Taija
Other contributor: University of Helsinki, Translational Cancer Biology (TCB) Research Programme



Date: 2018-04-03
Language: eng
Number of pages: 15
Belongs to series: Nature Communications
ISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-018-03692-0
URI: http://hdl.handle.net/10138/234564
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 postnatal 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-contactdependent 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.
Subject: ENDOTHELIAL-GROWTH-FACTOR
SPROUTING ANGIOGENESIS
DROSOPHILA TRACHEA
ARTERY FORMATION
TRANSGENIC MICE
FACTOR-C
NOTCH
LYMPHANGIOGENESIS
TIP
MOUSE
3111 Biomedicine
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