Published online before print December 21, 2007

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(American Journal of Pathology. 2008;172:37-49.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070130

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

Pascale Dufourcq^*, Lionel Leroux^*, Jérome Ezan^*, Betty Descamps^*, Jean-Marie Daniel Lamazière^*, Pierre Costet, Caroline Basoni, Catherine Moreau^*, Urban Deutsch^¶, Thierry Couffinhal^* and Cécile Duplàa^*

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.