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Departments of
Cardiovascular Pharmacology (T.-L.Y., X.W., S.G.,
K.P., J.-L.G., P.G.L., G.Z.F.) and
Toxicology (C.S.L., T.K.H.),
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406
2-Methoxyestradiol (2-ME) is an endogenous metabolite of
estradiol-17
and the oral contraceptive agent 17-ethylestradiol. 2-ME was recently reported to inhibit endothelial cell proliferation. The current study was undertaken to explore the mechanism of 2-ME effects on endothelial cells, especially whether 2-ME induces apoptosis, a prime mechanism in tissue remodeling and angiogenesis. Cultured bovine pulmonary artery endothelial cells (BPAEC) exposed to
2-ME showed morphological (including ultrastructural) features characteristic of apoptosis: cell shrinkage, cytoplasmic and nuclear condensation, and cell blebbing. 2-ME-induced apoptosis in BPAEC was a
time- and concentration-dependent process (EC50 = 0.45 ± 0.09 µM, n = 8). Nucleosomal DNA
fragmentation in BPAEC treated with 2-ME was identified by agarose gel
electrophoresis (DNA ladder) as well as in situ nick end
labeling. Under the same experimental conditions, estradiol-17 and
two of its other metabolites, estriol and 2-methoxyestriol (
10
µM), did not have an apoptotic effect on BPAEC. 2-ME
activated stress-activated protein kinase (SAPK)/c-Jun amino-terminal
protein kinase in BPAEC in a concentration-dependent manner. The
activity of SAPK was increased by 170 ± 27% and 314 ± 22%
over the basal level in the presence of 0.4 and 2 µM 2-ME (n = 3-6), respectively. The activation of SAPK
was detected at 10 min, peaked at 20 min, and returned to basal levels
at 60 min after exposure to 2-ME. Inhibition of SAPK/c-Jun
amino-terminal protein kinase activation by basic fibroblast growth
factor, insulin-like growth factor, or forskolin reduced 2-ME-induced
apoptosis. Immunohistochemical analysis of BPAEC indicated that 2-ME
up-regulated expression of both Fas and Bcl-2. In addition, 2-ME
inhibited BPAEC migration (IC50 = 0.71 ± 0.11 µM, n = 4) and basic fibroblast
growth factor-induced angiogenesis in the chick chorioallantoic
membrane model. Taken together, these results suggest that promotion of
endothelial cell apoptosis, thereby inhibiting endothelial cell
proliferation and migration, may be a major mechanism by which 2-ME
inhibits angiogenesis.
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