Adult tissue angiogenesis: Evidence for negative regulation by estrogen in the uterus

Increased uterine vascular permeability and angiogenesis are two major events of embryo implantation and placentation during pregnancy. These latter processes require coordinated, uterine-specific interactions between progesterone (P-4) and estrogen (E) signaling. Although roles of these steroids have long been suspected, definitive functions of E and/or P-4 in uterine angiogenesis still remain elusive. We have therefore exploited the availability of reporter and mutant mice to explore the regulation of angiogenesis in response to steroid hormonal changes in vivo. We present here molecular, genetic, physiological, and pharmacological evidence that E and P-4 have different effects in vivo: E promotes uterine vascular permeability but profoundly inhibits angiogenesis, whereas P-4 stimulates angiogenesis with little effect on vascular permeability. These effects of E and P-4 are mediated by differential spatiotemporal expression of proangiogenic factors in the uterus.