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Estrogen Enhances Angiogenesis through a Pathway Involving Platelet-Activating Factor-Mediated Nuclear Factor-B Activation

¹ Department of Biological Sciences, The Institute of Basic Sciences, Hormone Research Center, Chonnam National University, Kwangju, and ² Department of Immunology and Research Center for Allergic Immune Diseases, Chonbuk National University Medical School, Chonju, Republic of Korea

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-, 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)-B in HEC-1A cells and was also blocked by PAF antagonist. Inhibitors of NF-B 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-B 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-B activation.

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