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Izumi Suzuma, Michiko Mandai, Hitoshi Takagi, Kiyoshi Suzuma, Atsushi Otani, Hideyasu Oh, Kaori Kobayashi, Yoshihito Honda; 17 β-Estradiol Increases VEGF Receptor-2 and Promotes DNA Synthesis in Retinal Microvascular Endothelial Cells. Invest. Ophthalmol. Vis. Sci. 1999;40(9):2122-2129.
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purpose. Estrogen is known to promote angiogenesis in gonads. The presence of
estrogen receptors in the vascular endothelium of organs other than
gonads has been reported. The goal of this study was to determine
whether estrogen promotes the proliferation of retinal microvascular
endothelial cells and to explore the mechanism of it.
methods. DNA was quantitated using primary cultures of bovine retinal
endothelial cells that were incubated with different doses of 17β
-estradiol (E2), VEGF, or both. The changes in
expression level of VEGF and VEGF receptor-2 (VEGFR2) were measured
using northern blot analysis after treatment with E2. The
presence of estrogen receptors in the endothelial cells was studied by
immunohistochemistry and western blot analysis.
results. 17 β-Estradiol (E2) increased the DNA level in
bovine retinal capillary endothelial cells (BRECs) by 177% at 1 nM
(P < 0.05) and 150% at 10 nM
(P < 0.05) by comparison with unstimulated BREC.
One hundred nanomole tamoxifen completely blocked the
E2-induced DNA synthesis in BRECs. Ten nanomole
E2 augmented vascular endothelial growth factor
(VEGF)–induced DNA synthesis in BRECs significantly (160%, P < 0.01). Ten nanomole E2 also
increased VEGF mRNA expression, which peaked after 24 hours (6.7 times, P < 0.05), and VEGF receptor-2 (VEGFR2) mRNA
expression, which peaked after 9 hours (2.4 times, P < 0.05). The mRNA expression level of VEGFR2
peaked with 10 nM E2 (P < 0.05) and
that of VEGF reached maximum with 1 nM E2 (15 times, P < 0.001). VEGFR2 and VEGF proteins increased in
parallel with their mRNA levels. Immunocytochemistry showed estrogen
receptor expression in BRECs, and western blot analysis indicated the
presence of a 67-kDa protein that was compatible with the estrogen
conclusions. These findings suggest that E2 may stimulate BREC growth by
the receptor-mediated pathway and that E2 may augment the
VEGF-dependent angiogenesis partly through the upregulation of
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