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 RIS Download
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