Estrogen enhances angiogenesis through a pathway involving platelet-activating factor-mediated nuclear factor-kappaB activation.

Abstract

In this study, we investigated the molecular events involved in estrogen-induced angiogenesis. Treatment of the human endometrial adenocarcinoma cells, HEC-1A, with estrogen up-regulated mRNA expression and protein synthesis of various angiogenic factors such as tumor necrosis factor-alpha, interleukin-1, basic fibroblast growth factor, and vascular endothelial growth factor. The estrogen-dependent induction of the expression was blocked by the platelet-activating factor (PAF) antagonists, WEB 2170. Estrogen treatment caused the activation of nuclear factor (NF)-kappaB in HEC-1A cells and was also blocked by PAF antagonist. Inhibitors of NF-kappaB activation inhibited estrogen-induced mRNA expression and protein synthesis of the angiogenic factors. Estrogen led to a pronounced angiogenesis as assessed by a mouse Matrigel model in vivo and endothelial cell sprouting in vitro. PAF antagonists or NF-kappaB inhibitors significantly inhibited this estrogen-dependent angiogenesis. Estrogen caused phospholipase A2 (PLA2) gene and protein expression. Estrogen-induced vascular endothelial growth factor mRNA expression and sprouting were significantly inhibited by PLA2 inhibitors, suggesting PLA2 expression is the upstream pathway in the estrogen-induced angiogenesis. Taken together, these results suggest that estrogen induces the production of angiogenic factors via a mechanism involving PAF-mediated NF-kappaB activation.