Ovariectomy, but not estrogen deficiency, increases CYP4A modulation of α₁-adrenergic vasoconstriction in aging female rats

Background: Postmenopausal women are more likely to develop cardiovascular disease (CVD) than premenopausal women. Increased vasoconstriction in the peripheral vasculature may underlie this risk. In vascular smooth muscle, cytochrome P450 4A (CYP4A) enzymes form the vasoconstrictor 20- hydroxyeicosatetraenoic acid (20-HETE). CYP4A modulation of α₁- adrenergic vasoconstriction is increased in aging male rats; however, this pathway has not been investigated in aging females. To generate an appropriate model of menopause, we ovariectomized aged Sprague-Dawley rats to create an aged, ovarian-depleted phenotype. Because estrogen has profound effects on the peripheral vasculature, we also determined the effect of estrogen replacement on CYP4A modulation of vasoconstriction. Methods: Aged (15-16 months) rats were assigned to be intact or ovariectomized. Ovariectomized rats received either placebo (OVX) or 17β-estradiol (OVX-E) subcutaneously for 4 weeks. Mesenteric arteries were isolated and constricted with the α₁- adrenergic agonist phenylephrine or intraluminal pressure in the absence or presence of the CYP4A inhibitor, DDMS. Results: Ovariectomy increased CYP4A modulation of α₁-adrenergic vasoconstriction. This was unaffected by estrogen replacement. Arteries from OVX-E animals exhibited increased phenylephrine sensitivity and forced dilation relative to arteries from intact and OVX animals. Myogenic tone was increased in both OVX and OVX-E animals relative to intact rats; however, CYP4A inhibition had no effect on myogenic tone in any group. Conclusions: In aged female rats, ovariectomy caused an increase in CYP4A modulation of α₁-adrenergic vasoconstriction that was not prevented by estrogen replacement. Future study of these pathways may provide important targets for the prevention of CVD in aging women.