Estrogen promotes endothelial cell proliferation and survival in the vasculture of non-reproductive organs. The main mechanisms through which estrogen exerts its effects on endothelial cells remain unknown. Angiopoietins are newly described modulators of endothelial cell survival and they exert their effects through the activation of endothelial cell-specific Tie-2 receptors. In this study, we evaluated whether estrogen modulates the activity and expression of Tie-2 receptors, Ang-1 and its endogenous antagonist; angiopoietins-2 (Ang-2) in non-reproductive organs. Using RT-PCR, we found that daily administration of 17-beta-estradiol for 8 days in ovariectomized rats results in a significant reduction in tissue Ang-1 mRNA expression. By comparison, estrogen therapy produced a significant increase in Ang-2 mRNA in estrogen-treated rats with heart, kidney and lung Ang-2 mRNA levels reaching 169%, 152% and 224% of those of oil-treated animals, respectively. We also observed that tyrosine phosphorylation of Tie-2 receptors is significantly attenuated in ovariectomized rats treated with 17-beta-estradiol. Our results suggest that the effects of estrogen on the vasculature of non-reproductive organs require the inhibition of angiopoietin-1-Tie-2 receptor pathway and that this inhibition is achieved through simultaneous down-regulation of Ang-1 and Tie-2 expression and elevation in Ang-2 expression.