Genistein restores caveolin-1 and AT-1 receptor expression and vascular function in large vessels of ovariectomized hypertensive rats.
OBJECTIVE
The soy-derived phytoestrogen genistein improves endothelial function in postmenopausal women and ovariectomized (OVX) normotensive rats. We hypothesized that genistein would improve vascular reactivity involving changes in endothelial nitric oxide synthase (NOS) expression and its regulatory proteins (caveolin and calmodulin), angiotensin II receptor, and/or oxidative status in OVX spontaneously hypertensive rats (SHRs).


METHODS
After ovariectomy or sham operation, 23-week-old female SHRs received either 17beta-estradiol (2 mg/kg/wk SC), genistein (10 mg/kg/d by gavage), or placebo.


RESULTS
In OVX rats, final body weight was increased and uterus weight was decreased, and these values were reduced and increased, respectively, by 17beta-estradiol but unaffected by genistein. Acetylcholine-induced endothelium-dependent vasorelaxation was significantly blunted in aortas from OVX placebo SHRs. The contractions induced by the NOS inhibitor L-NAME and angiotensin II in OVX placebo were lower and higher, respectively, than in sham rats. Estradiol and genistein restored these functional changes. Aortic endothelial NOS and calmodulin-1 expression were unchanged, whereas caveolin-1 and angiotensin II receptor expression was increased in OVX rats. Estradiol and genistein treatment did not modify endothelial NOS, but normalized caveolin-1 and angiotensin II receptor and increased calmodulin-1 expression. Vascular superoxide production was increased in OVX placebo and normalized by both estradiol and genistein.


CONCLUSIONS
Genistein prevented all cardiovascular changes induced by estrogen depletion in SHRs to a similar extent as estradiol but had no uterotrophic effect. The present findings may help to explain the potential benefits of genistein as a therapeutic agent for preventing menopausal vascular complications, especially in hypertensive women.
Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain.
Rocio
R
Vera
Rosario
R
Jiménez
Federica
F
Lodi
Manuel
M
Sánchez
Milagros
M
Galisteo
Antonio
A
Zarzuelo
Francisco
F
Pérez-Vizcaíno
Juan
J
Duarte
D000818:Animals; D001011:Aorta / Q000187:drug effects; D051242:Caveolin 1 / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D019833:Genistein / Q000008:administration & dosage / Q000494:pharmacology*; D010052:Ovariectomy; D048789:Phytoestrogens / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D051242:Caveolin 1; D048789:Phytoestrogens; D044140:Receptor, Angiotensin, Type 1; D014665:Vasodilator Agents; D019833:Genistein