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Published online before print December 21, 2007
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From INSERM U828,*Pessac, France; the Centre de Transgenose,
Université Victor Ségalen Bordeaux 2, Bordeaux, France; the Department of Cardiology,
Hôpital Haut Lévêque, Pessac, France; Institut Européen de Chemie et Biologie (IECB),
Pessac, France; and the Theodor Kocher Institute,¶University Bern, Bern, Switzerland
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-3β. sFRP-1 overexpression in endothelium specifically reversed the inactivation of GSK-3β and increased neovascularization in ischemia-induced angiogenesis in mouse hindlimb. This study illustrates a regulated pathway by sFRP-1 involving GSK-3β and Rac-1 in endothelial cell cytoskeletal reorganization and in neovessel formation.
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