Extracellular signal-regulated kinase 1/2 activation, via downregulation of mitogen-activated protein kinase phosphatase 1, mediates sex differences in desoxycorticosterone acetate-salt hypertension vascular reactivity

Fernanda R. Giachini, Jennifer C. Sullivan, Victor V. Lima, Fernando S. Carneiro, Zuleica B. Fortes, David M. Pollock, Maria Helena C. Carvalho, R. Clinton Webb, Rita C. Tostes

Research output: Contribution to journalArticle

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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 (191±3 mm Hg) compared with female DOCA rats (172±7 mm Hg; n=5). DOCA treatment resulted in augmented contractile responses to phenylephrine in aorta (22±3 mN; n=6) and small mesenteric arteries (13±2 mN; n=6) from male DOCA rats versus uninephrectomized male rats (16±3 and 10±2 mN, respectively; P<0.05) and female DOCA rats (15±1 and 11±1 mN, respectively). ERK1/2 inhibition with PD-98059 (10 μmol/L) abrogated increased contraction to phenylephrine in aorta (14±2 mN) and small mesenteric arteries (10±2 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 hypertensive rats is mediated via activation of the ERK1/2 pathway. In addition, mitogen-activated protein kinase phosphatase 1 and interleukin 10 play regulatory roles in this process.

Original languageEnglish (US)
Pages (from-to)172-179
Number of pages8
JournalHypertension
Volume55
Issue number1
DOIs
StatePublished - Jan 1 2010

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Keywords

  • ERK1/2
  • Hypertension
  • MKP-1
  • Sex differences
  • Vascular reactivity

ASJC Scopus subject areas

  • Internal Medicine

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