20‐Hydroxyeicosatetraenoic acid modulation of vasoconstriction in aged female rats is increased by ovariectomy but not estrogen deficiency

Menopause triggers a dramatic increase in the risk of cardiovascular disease. Elevated vasoconstrictor activity in peripheral arteries may underlie this risk. 20‐Hydroyeicosatetraenoic acid (20‐HETE) is a potent vasoconstrictor formed by cytochrome P450 4A (CYP4A) enzymes. Aging increases 20‐HETE modulation of vasoconstriction in male rats, but its effects in female rats are unknown. We hypothesized that, in aged rats, the contribution of 20‐HETE to vasoconstriction would be increased by ovariectomy (simulated menopause) and that estrogen replacement would reduce this contribution. Small mesenteric arteries were isolated from aged (14 months) intact and ovariectomized rats. Ovariectomized rats received either placebo (OVX‐P) or 17β‐estradiol (OVX‐E) for 4 weeks. Arterial responses to phenylephrine (PE) were assessed in the presence or absence of the CYP4A inhibitor DDMS (10μM). In agreement with our hypothesis, CYP4A inhibition reduced PE sensitivity in OVX‐P rats (EC 50 :0.57±0.10 vs. 0.91±0.24μM, P = 0.040) but had no effect on arteries from intact rats. Interestingly, CYP4A inhibition also reduced arterial PE sensitivity in OVX‐E rats (EC 50 :0.48±0.03 vs. 0.83±0.21μM, P = 0.046). Therefore, the contribution of 20‐HETE to vasoconstriction is elevated by ovariectomy, but not estrogen deficiency, in aged rats. Further study may explain the deleterious, estrogen‐independent, effects of menopause. Funded by CIHR