Extracellular Signal–Regulated Kinase 1/2 Activation, via Downregulation of Mitogen-Activated Protein Kinase Phosphatase 1, Mediates Sex Differences in

Abstract—Extracellular signal–regulated kinase (ERK)1/2 has been reported to play a role in vascular dysfunction associated with mineralocorticoid hypertension. We hypothesized that, compared with female rats, an upregulation of ERK1/2 signaling in the vasculature of male rats contributes to augmented contractile responses in mineralocorticoid hypertension. Uninephrectomized male and female Sprague-Dawley rats received desoxycorticosterone acetate (DOCA) pellets (200 mg per animal) and saline to drink for 3 weeks. Control uninephrectomized rats received tap water to drink. Blood pressure, measured by telemetry, was significantly higher in male DOCA rats (1913 mm Hg) compared with female DOCA rats (1727 mm Hg; n5). DOCA treatment resulted in augmented contractile responses to phenylephrine in aorta (223 mN; n6) and small mesenteric arteries (132 mN; n6) from male DOCA rats versus uninephrectomized male rats (163 and 102 mN, respectively; P0.05) and female DOCA rats (151 and 111 mN, respectively). ERK1/2 inhibition with PD-98059 (10 mol/L) abrogated increased contraction to phenylephrine in aorta (142 mN) and small mesenteric arteries (102 mN) from male DOCA rats, without any effects in arteries from male uninephrectomized or female animals. Compared with the other groups, phosphorylated ERK1/2 levels were increased in the aorta from male DOCA rats, whereas mitogen-activated protein kinase phosphatase 1 expression was decreased. Interleukin-10 plasma levels, which positively regulate mitogen-activated protein kinase phosphatase 1 activity, were reduced in male DOCA-salt rats. We speculate that augmented vascular reactivity in male hypertensiv