Netrin-4 promotes mural cell adhesion and recruitment to endothelial cells

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Esma Lejmi Ilyes Bouras Serge Camelo Marie Roumieux Norbert Minet Carole Leré-Déan Tatyana Merkulova-Rainon Gwennhael Autret Catherine Vayssettes Olivier Clement Jean Plouët Laurence Leconte



Netrins are secreted molecules involved in axon guidance and angiogenesis. We previously showed that Netrin-4 acts as an anti-angiogenic factor by inhibiting endothelial cell (EC) functions. In this study, we investigated the effects of Netrin-4 on vascular smooth muscle cell (VSMC) activity in vitroand in vivo. We show that exogenous Netrin-4 stimulated VSMC adhesion and migration, and increased their coverage on EC tubes (grown on a Matrigel substrate). siRNA knock-down of endogenous Netrin-4 expression in VSMC decreased their recruitment to EC tubes. VSMC expressed Netrin-4 and three of the six Netrin-1 cognate receptors: DCC, Neogenin, and Unc5B. Silencing of these receptors reduced Netrin-4 adhesion to VSMC, strongly suggesting that these receptors were involved in the recruitment process. We previously showed that Netrin-4 overexpression in PC3 cancer cells delayed tumor growth in a model of subcutaneous xenograft by reducing tumor vessel density. Here, we show that Netrin-4 overexpression improved tumor blood vessel structure and increased VSMC coverage. Thus, Netrin-4 induced mural cell recruitment may play a role in the inhibition of tumor growth. Our data suggest that Netrin-4 is important for blood vessel normalization through the regulation of both endothelial and perivascular cells.

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LEJMI, Esma et al. Netrin-4 promotes mural cell adhesion and recruitment to endothelial cells. Vascular Cell, [S.l.], v. 6, n. 1, p. 1, jan. 2014. ISSN 2045-824X. Available at: <>. Date accessed: 20 jan. 2022. doi:
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