Netrin-4 promotes mural cell adhesion and recruitment to endothelial cells.
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 vitro and 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.
Esma
E
Lejmi
Ilyes
I
Bouras
Serge
S
Camelo
Marie
M
Roumieux
Norbert
N
Minet
Carole
C
Leré-Déan
Tatyana
T
Merkulova-Rainon
Gwennhael
G
Autret
Catherine
C
Vayssettes
Olivier
O
Clement
Jean
J
Plouët
Present address: SISENE, Pépinière Paris Santé Cochin, 29 rue du Faubourg Saint Jacques, Paris 75014, France. laurence.leconte@yahoo.fr.
Laurence
L
Leconte