Dietary sodium restriction sex specifically impairs endothelial function via mineralocorticoid receptor-dependent reduction in NO bioavailability in Balb/C mice

Jessica L. Faulkner, Daisy Harwood, Simone Kennard, Galina Antonova, Nicolas Clere, Eric J.Belin De Chantemele

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Recent findings from our group demonstrated that females exhibit higher endothelial mineralocorticoid receptor (MR) expression than males, which predisposes them to aldosterone-mediated endothelial dysfunction in the context of metabolic disorders. However, whether the endothelium of female mice presents a higher propensity to MR-mediated dysfunction than that of males in the absence of comorbidities remains unknown. We therefore sought to investigate whether increasing aldosterone production endogenously with sodium restriction impairs endothelial function in otherwise healthy female mice. We fed male and female Balb/C mice a normal (0.4% NaCl; NSD) or sodium-restricted diet (0.05% NaCl; SRD) for 4 wk. Females exhibited higher baseline endothelial function (relaxation to acetylcholine) and lower vascular contractility (constriction to phenylephrine, serotonin, and KCl). However, SRD impaired endothelial-dependent relaxation and increased vascular contractility in female mice, effectively ablating the baseline sex difference. Female sex also increased baseline adrenal CYP11B2 expression; however, SRD significantly enhanced CYP11B2 expression in male and female mice and ablated the sex difference. Nitric oxide synthase (NOS) inhibition with Nx-nitro-L-arginine methyl ester hydrochloride eliminated both sex as well as diet-induced differences in endothelial dysfunction. In accordance, females demonstrated higher vascular endothelial NOS expression at baseline, which SRD significantly decreased. In addition, SRD diminished vascular NOX4 expression in female mice only. MR blockade with spironolactoneprotected female mice from decreases in endothelial-dependent relaxation but not increases in vascular contractility. Utilizing sodium restriction as a method to increase plasma aldosterone levels in healthy female mice, we demonstrated that female mice are more susceptible to vascular damage via MR activation in the vascular endothelium only.

Original languageEnglish (US)
Pages (from-to)H211-H220
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume320
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • Aldosterone
  • Cyp11b2
  • Endothelial function
  • Mineralocorticoid receptor
  • Sex differences
  • Vascular function

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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