Ovarian ablation alone promotes aortic intimal hyperplasia and accumulation of fibroblast growth factor.
BACKGROUND
Estrogen-mediated cardiovascular protection is incompletely explained by its beneficial lipid-modifying effects. Previous studies interrogating direct vascular effects of estrogens have used models of either diet- or injury-induced atherosclerosis. The purpose of this study was to determine the influence of ovarian ablation alone on vascular remodeling. We hypothesized that estrogens are atheroprotective, independent of their influence on lipid metabolism, by directly influencing the production and effects of a prototypical atherogenic mediator, basic fibroblast growth factor (bFGF).


RESULTS
Twenty-five female sheep were randomized to sham operation, ovariectomy, or ovariectomy plus 17beta-estradiol replacement. Serum cholesterol and triglyceride levels were serially measured for 1 year and were similar among groups and in the normal range (30 to 60 mg/dL). At 6, 9, and 12 months, ovariectomy resulted in aortoiliac intimal hyperplasia compared with sham (P<0.01) and hormone replacement (P<0.01) groups. The neointima of ovariectomized animals was characterized immunohistochemically by increased vascular smooth muscle cells (VSMCs). Levels of bFGF protein were determined in adjacent aortic segments. Ovariectomized sheep had 2-fold more FGF than sham or ovariectomized sheep that received hormone replacement. In vitro, estradiol inhibited the mitogenic effect of bFGF on human aortic VSMCs.


CONCLUSIONS
Without dietary manipulation, ovarian ablation alone induces aortic intimal hyperplasia in the ewe. Estradiol abrogates this response independently of its effects on serum lipids. Hormone replacement decreases the accumulation of the atherogenic peptide bFGF in vivo and inhibits the mitogenic response of VSMCs to bFGF in vitro. These results suggest that estrogens may provide atheroprotection both by modulating local production and by attenuating the influence of bFGF on VSMC growth.
Selzman
C H
CH
Departments of Surgery and Medicine , University of Colorado Health Sciences Center, Denver, CO, USA. craig.selzman@uchsc.edu
Gaynor
J S
JS
Turner
A S
AS
Johnson
S M
SM
Horwitz
L D
LD
Whitehill
T A
TA
Harken
A H
AH
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D010052:Ovariectomy / Q000009:adverse effects*; D012756:Sheep; D017539:Tunica Intima / Q000473:pathology*
D004958:Estradiol; D005346:Fibroblast Growth Factors