TY - JOUR
T1 - Dietary sodium restriction sex specifically impairs endothelial function via mineralocorticoid receptor-dependent reduction in NO bioavailability in Balb/C mice
AU - Faulkner, Jessica L.
AU - Harwood, Daisy
AU - Kennard, Simone
AU - Antonova, Galina
AU - Clere, Nicolas
AU - Chantemele, Eric J.Belin De
N1 - Funding Information:
This work was supported by National Institutes of Health Grants 1R01-HL-130301-01 and 1R01-HL-147639-01A1 (to E.J.B.) and 5F32HL-136191-02 and 1K99 H-L146948-01 (to J.L.F.) and American Heart Association Grant 19EIA34760167.
Publisher Copyright:
Copyright © 2021 the American Physiological Society.
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - Aldosterone
KW - Cyp11b2
KW - Endothelial function
KW - Mineralocorticoid receptor
KW - Sex differences
KW - Vascular function
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U2 - 10.1152/AJPHEART.00413.2020
DO - 10.1152/AJPHEART.00413.2020
M3 - Article
C2 - 33095056
AN - SCOPUS:85099428181
SN - 0363-6135
VL - 320
SP - H211-H220
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 1
ER -