Inhibition of angiogenesis by a mouse sprouty protein

Sprouty negatively modulates branching morphogenesis in the Drosophila trac heal system. To address the role of mammalian Sprouty homologues in angioge nesis, another form of branching morphogenesis, a recombinant adenovirus en gineered to express murine Sprouty-4 selectively in endothelial cells, was injected into the sinus venosus of embryonic day 9.0 cultured mouse embryos . Sprouty-4 expression inhibited branching and sprouting of small vessels, resulting in abnormal embryonic development. In vitro, Sprouty-4 inhibited fibroblast growth factor and vascular endothelial cell growth factor-mediat ed cell proliferation and migration and prevented basic fibroblast growth f actor and vascular endothelial cell growth factor-induced MAPK phosphorylat ion in endothelial cells, indicating inhibition of tyrosine kinase-mediated signaling pathways. The ability of constitutively activated mutant Ras(L61 ) to rescue Sprouty-4 inhibition of MAPK phosphorylation suggests that Spro uty inhibits receptor tyrosine kinase signaling upstream of Ras. Thus, Spro uty may regulate angiogenesis in normal and disease processes by modulating signaling by endothelial tyrosine kinases.