Regulation of endothelial cell cytoskeletal reorganization by a secreted frizzled-related protein-1 and frizzled 4-and frizzled 7-dependent pathway: Role in neovessel formation
The American Journal of Pathology. 2008-01-01; 172(1): 37-49
DOI: 10.2353/ajpath.2008.070130
Lire sur PubMed
Dufourcq P(1), Leroux L, Ezan J, Descamps B, Lamazière JM, Costet P, Basoni C, Moreau C, Deutsch U, Couffinhal T, Duplàa C.
Author information:
(1)INSERM U828, Av du haut lévèque, 33600 Pessac, France.
Consistent with findings of Wnt pathway members involved in vascular cells, a
role for Wnt/Frizzled signaling has recently emerged in vascular cell
development. Among the few Wnt family members implicated in vessel formation in
adult, Wnt7b and Frizzled 4 have been shown as involved in vessel formation in
the lung and in the retina, respectively. Our previous work has shown a role for
secreted Frizzled-related protein-1 (sFRP-1), a proposed Wnt signaling inhibitor,
in neovascularization after an ischemic event and demonstrated its role as a
potent angiogenic factor. However the mechanisms involved have not been
investigated. Here, we show that sFRP-1 treatment increases endothelial cell
spreading on extracellular matrix as revealed by actin stress fiber
reorganization in an integrin-dependent manner. We demonstrate that sFRP-1 can
interact with Wnt receptors Frizzled 4 and 7 on endothelial cells to transduce
downstream to cellular machineries requiring Rac-1 activity in cooperation with
GSK-3beta. sFRP-1 overexpression in endothelium specifically reversed the
inactivation of GSK-3 beta and increased neovascularization in ischemia-induced
angiogenesis in mouse hindlimb. This study illustrates a regulated pathway by
sFRP-1 involving GSK-3beta and Rac-1 in endothelial cell cytoskeletal
reorganization and in neovessel formation.