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

Am J Pathol. 2008 Jan;172(1):37-49. doi: 10.2353/ajpath.2008.070130. Epub 2007 Dec 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Actins
  • FZD4 protein, human
  • FZD7 protein, human
  • Frizzled Receptors
  • Proteins
  • Receptors, G-Protein-Coupled
  • frizzled related protein-1
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3