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
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Dufourcq P(1), Leroux L, Ezan J, Descamps B, Lamazière JM, Costet P, Basoni C, Moreau C, Deutsch U, Couffinhal T, Duplàa C.
(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.