Estrogen enhances angiogenesis through a pathway involving platelet-activating factor-mediated nuclear factor-kappaB activation.
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.
Seo
Kook Heon
KH
Department of Biological Sciences, The Institute of Basic Sciences, Hormone Research Center, Chonnam National University, Kwangju, Republic of Korea.
Lee
Hyun-Suk
HS
Jung
Bongnam
B
Ko
Hyun-Mi
HM
Choi
Jung-Hwa
JH
Park
Sung Jun
SJ
Choi
Il-Hwan
IH
Lee
Hern-Ku
HK
Im
Suhn-Young
SY
D000230:Adenocarcinoma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016889:Endometrial Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D045166:Estradiol Congeners / Q000494:pharmacology*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D010741:Phospholipases A / Q000096:biosynthesis / Q000235:genetics; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D045166:Estradiol Congeners; D007375:Interleukin-1; D016209:Interleukin-8; D016328:NF-kappa B; D010972:Platelet Activating Factor; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D010741:Phospholipases A; D054467:Phospholipases A2