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Rspo1/Wnt signaling promotes angiogenesis via Vegfc/Vegfr3.

Here, we show that a novel Rspo1-Wnt-Vegfc-Vegfr3 signaling pathway plays an essential role in developmental angiogenesis. A mutation in R-spondin1 (rspo1), a Wnt signaling regulator, was uncovered during a forward-genetic screen for angiogenesis-deficient mutants in the zebrafish. Embryos lacking rspo1 or the proposed rspo1 receptor kremen form primary vessels by vasculogenesis, but are defective in subsequent angiogenesis. Endothelial cell-autonomous inhibition of canonical Wnt signaling also blocks angiogenesis in vivo. The pro-angiogenic effects of Rspo1/Wnt signaling are mediated by Vegfc/Vegfr3(Flt4) signaling. Vegfc expression is dependent on Rspo1 and Wnt, and Vegfc and Vegfr3 are necessary to promote angiogenesis downstream from Rspo1-Wnt. As all of these molecules are expressed by the endothelium during sprouting stages, these results suggest that Rspo1-Wnt-VegfC-Vegfr3 signaling plays a crucial role as an endothelial-autonomous permissive cue for developmental angiogenesis.

Pubmed ID: 22007135


  • Gore AV
  • Swift MR
  • Cha YR
  • Lo B
  • McKinney MC
  • Li W
  • Castranova D
  • Davis A
  • Mukouyama YS
  • Weinstein BM


Development (Cambridge, England)

Publication Data

November 26, 2011

Associated Grants

  • Agency: NICHD NIH HHS, Id: HD001011

Mesh Terms

  • Animals
  • Animals, Genetically Modified
  • Cells, Cultured
  • Embryo, Nonmammalian
  • Gene Expression Regulation, Developmental
  • Models, Biological
  • Neovascularization, Pathologic
  • Neovascularization, Physiologic
  • Up-Regulation
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3
  • Wnt Proteins
  • Wnt Signaling Pathway
  • Zebrafish
  • Zebrafish Proteins