Wnt5a signaling induces proliferation and survival of endothelial cells in vitro and expression of MMP-1 and Tie-2

Mol Biol Cell. 2006 Dec;17(12):5163-72. doi: 10.1091/mbc.e06-04-0320. Epub 2006 Oct 11.


Wnts are lipid-modified secreted glycoproteins that regulate diverse biological processes. We report that Wnt5a, which functions in noncanonical Wnt signaling, has activity on endothelial cells. Wnt5a is endogenously expressed in human primary endothelial cells and is expressed in murine vasculature at several sites in mouse embryos and tissues. Expression of exogenous Wnt5a in human endothelial cells promoted angiogenesis. Wnt5a induced noncanonical Wnt signaling in endothelial cells, as measured by Dishevelled and ERK1/2 phosphorylation, and inhibition of canonical Wnt signaling, a known property of Wnt5a. Wnt5a induced endothelial cell proliferation and enhanced cell survival under serum-deprived conditions. The Wnt5a-mediated proliferation was blocked by Frizzled-4 extracellular domain. Wnt5a expression enhanced capillary-like network formation, whereas reduction of Wnt5a expression decreased network formation. Reduced Wnt5a expression inhibited endothelial cell migration. Screening for Wnt5a-regulated genes in cultured endothelial cells identified several encoding angiogenic regulators, including matrix metalloproteinase-1, an interstitial collagenase, and Tie-2, a receptor for angiopoietins. Thus, Wnt5a acts through noncanonical Wnt signaling to promote angiogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Blood Vessels / metabolism
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Dishevelled Proteins
  • Endothelial Cells / cytology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Frizzled Receptors / genetics
  • Gene Expression Regulation
  • Humans
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 1 / metabolism*
  • Mice
  • Microarray Analysis
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, TIE-2 / genetics
  • Receptor, TIE-2 / metabolism*
  • Signal Transduction*
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • Wnt-5a Protein


  • Adaptor Proteins, Signal Transducing
  • Dishevelled Proteins
  • Frizzled Receptors
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • WNT5A protein, human
  • Wnt Proteins
  • Wnt-5a Protein
  • Wnt5a protein, mouse
  • Receptor, TIE-2
  • Extracellular Signal-Regulated MAP Kinases
  • Matrix Metalloproteinase 1