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.

Abstract

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.

• Authors: Pascale Dufourcq, Lionel Leroux, Jérome Ezan, Betty Descamps, Jean-Marie Daniel Lamazière, Pierre Costet, Caroline Basoni, Catherine Moreau, Urban Deutsch, Thierry Couffinhal, Cécile Duplàa
• Journal: The American journal of pathology (Am J Pathol) Vol. 172 Issue 1 Pg. 37-49 (Jan 2008) ISSN: 0002-9440 [Print] United States
• PMID: 18156211 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• FZD4 protein, human
• FZD7 protein, human
• Frizzled Receptors
• Intracellular Signaling Peptides and Proteins
• Proteins
• Receptors, G-Protein-Coupled
• WD repeat containing planar cell polarity effector
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3

Topics

• Actins (metabolism)
• Animals
• Endothelial Cells (cytology, pathology)
• Endothelium, Vascular (cytology, metabolism)
• Frizzled Receptors (biosynthesis)
• Gene Expression Regulation
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Intracellular Signaling Peptides and Proteins
• Mice
• Models, Biological
• Neovascularization, Pathologic
• Proteins (metabolism, physiology)
• Receptors, G-Protein-Coupled (biosynthesis)
• Signal Transduction
• Swine