Secreted frizzle-related protein 2 (SFRP2), a modulator of Wnt-signaling, has recently been found to be overexpressed in the vasculature of 85% of human breast tumors, however its role in angiogenesis is unknown. We found that SFRP2 induced angiogenesis in the mouse Matrigel plug assay and the chick chorioallantoic membrane assay. SFRP2 inhibited hypoxia induced endothelial cell apoptosis, increased endothelial cell migration, and induced endothelial tube formation. The canonical Wnt-pathway was not affected by SFRP2 in endothelial cells, however, a component of the non-canonical Wnt/Ca++ pathway was affected by SFRP2, as demonstrated by an increase in NFATc3 in the nuclear fraction of SFRP2-treated endothelial cells. Tacrolimus, a calcineurin inhibitor which inhibits dephosphorylation of NFAT, inhibited SFRP2-induced endothelial tube formation. Tacrolimus 3 mg/kg/daily inhibited the growth of SVR angiosarcoma xenografts in mice by 46% (p=0.04). In conclusion, SFRP2 is a novel stimulator of angiogenesis that stimulates angiogenesis via a calcineurin/NFAT pathway, and may be a favorable target for the inhibition of angiogenesis in solid tumors
