| J Steroid Biochem Mol Biol 88:101-110, 2004 |
|
| High glucose blocks the effects of estradiol on human vascular cell
growth: differential interaction with estradiol and raloxifene |
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| Dalia Somjen , Channing J. Paller , Batya Gayer , Fortune Kohen ,
Esther Knoll and Naftali Stern |
|
| a Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv
Sourasky Medical Center, and Sackler Faculty of Medicine Tel Aviv University,
6 Weizman Street, Tel Aviv 64239, Rehovot, Israel |
|
Because diabetic women appear not to be protected by estrogen in
terms of propensity to cardiovascular disease, we tested the possibility
that chronic hyperglycemia modulates the effects of E2 on vascular
cell growth in vitro. Human endothelial cells (E304) and vascular smooth
muscle cells (VSMC) were grown in normal glucose (5.5 mmol/l), high
glucose (22 mmol/l) or high manitol (22 nmol/l; an osmotic control)
for 7 days. In endothelial cells glucose per se stimulated DNA synthesis.
However E2- (but not RAL-) stimulated [3H] thymidine incorporation
was attenuated in the presence of high glucose. In parallel, E2-dependent
MAP-kinase-kinase activity was blocked in the presence of high glucose.
High glucose increased basal creatine kinase (CK) specific activity,
but E2-stimulated CK was not significantly impaired in the presence
of high glucose. In VSMC, high glucose prevented the inhibitory effect
of high E2 (but not of high RAL) concentrations on DNA synthesis. High
glucose also prevented E2-induced MAP-kinase-kinase activity. In contrast,
while high glucose augmented basal CK, the relative E2-induced changes
were roughly equal in normal and high high glucose media. Hence, high
glucose blocks several effects of E2 on vascular cell growth, which
are mediated, in part, via the MAP-kinase system and are likely contributors
to E2's anti-atherosclerotic properties. Since RAL's estrogen-mimetic
effects on human vascular cell growth were independent of MAP-kinase
activation and were not affected by hyperglycemia, the potential use
of RAL to circumvent the loss of estrogen function induced by hyperglycemia
and diabetes in the human vasculature should be further explored.
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