Long-term effects of ovariectomy and estrogen replacement treatment on endothelial function in mature rats.
OBJECTIVE
Estrogen replacement therapy (ERT) improves blood flow through various mechanisms including an augmented release of nitric oxide (NO). We report on the long-term effects of estrogen loss on vascular function and endothelial regulation.


METHODS
Male, female, ovariectomized and ovariectomized+ERT treated rats were used. Female rats were ovariectomized at 12 weeks of age and received ERT via subcutaneously implanted 90-day release pellets. Vasodilation to acetylcholine (ACh) was studied in tail artery segments; arterial blood was collected for measurements of 17-beta-estradiol and stable metabolites of NO (nitrate/nitrite). Some arterial segments were harvested for TUNEL staining to determine endothelial apoptosis.


RESULTS
Ovariectomy caused a rapid loss of estradiol that was negated by ERT. Likewise, there was also a loss in plasma NO. Loss of ACh-mediated dilations were age-dependent and were significant in males and untreated ovariectomized rats, with the change being maximal after 12 weeks of ovariectomy. After 12 weeks post-ovariectomy, there were no time dependent changes in ACh sensitivity in either group. Dilations to ACh were maintained in females and age-matched ERT ovariectomized rats over time. TUNEL staining of the endothelium (at 6 months of age) revealed apoptotic changes with the rank order male>ovariectomized>female, or ERT treated ovariectomized female rats.


CONCLUSIONS
In a rat model of surgical menopause, loss of endothelial function is maximal 12 weeks after ovariectomy. Apoptosis of endothelial cells is greatest in arteries from male rats. Our data suggests that early ERT treatment may be an important consideration for reducing endothelium-dependent vascular dysfunction.
Moien-Afshari
Farzad
F
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, 2176 Health Sciences Mall,Vancouver, BC, Canada V6T 1Z3.
Kenyon
Emma
E
Choy
Jonathan C
JC
Battistini
Bruno
B
McManus
Bruce M
BM
Laher
Ismail
I
D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging; D000818:Animals; D017209:Apoptosis; D004730:Endothelium, Vascular / Q000502:physiology*; D004958:Estradiol / Q000097:blood; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000097:blood / Q000502:physiology*; D005260:Female; D008297:Male; D023421:Models, Animal; D009569:Nitric Oxide / Q000097:blood; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation
D004967:Estrogens; D009569:Nitric Oxide; D004958:Estradiol; D000109:Acetylcholine