High-salt diet augments systolic blood pressure and induces arterial dysfunction in outbred, genetically diverse mice

Abstract

Excess salt consumption contributes to hypertension and arterial dysfunction in humans living in industrialized societies. However, this arterial phenotype is not typically observed in inbred, genetically identical mouse strains that consume a high-salt (HS) diet. Therefore, we sought to determine the effects of HS diet consumption on systolic blood pressure (BP) and arterial function in UM-HET3 mice, an outbred, genetically diverse strain of mice. Male and female UM-HET3 mice underwent a low-salt [LS (1% NaCl)] or HS (4% NaCl) diet for 12 wk. Systolic BP and aortic stiffness, determined by pulse wave velocity (PWV), were increased in HS after 2 and 4 wk, respectively, compared with baseline and continued to increase through week 12 (P < 0.05). Systolic BP was higher from weeks 2-12 and PWV was higher from weeks 4-12 in HS compared with LS mice (P < 0.05). Aortic collagen content was ∼81% higher in HS compared with LS (P < 0.05), whereas aortic elastin content was similar between groups (P > 0.05). Carotid artery endothelium-dependent dilation (EDD) was ∼10% lower in HS compared with LS (P < 0.05), endothelium-independent dilation was similar between groups (P > 0.05). Finally, there was a strong relationship between systolic BP and PWV (r² = 0.40, P < 0.05), as well as inverse relationship between EDD and systolic BP (r² = 0.21, P < 0.05) or PWV (r² = 0.20, P < 0.05). In summary, HS diet consumption in UM-HET3 mice increases systolic BP, which is accompanied by aortic stiffening and impaired EDD. These data suggest that outbred, genetically diverse mice may provide unique translational insight into arterial adaptations of humans that consume an HS diet.NEW & NOTEWORTHY Excess salt consumption is a contributor to hypertension and arterial dysfunction in humans living in industrialized societies, but this phenotype is not observed in inbred, genetically identical mice that consume a high-salt (HS) diet. This study reveals that a HS diet in outbred, genetically diverse mice progressively increases systolic blood pressure and induce arterial dysfunction. These data suggest that genetically diverse mice may provide translational insight into arterial adaptations in humans that consume an HS diet.

Keywords: aortic stiffness; diet; endothelium; hypertension; salt.

Figure 1.

Group comparisons in low-salt (LS) and high-salt (HS) diet-treated mice. Data were analyzed using unpaired t test to identify differences in urine sodium (A), chloride (B), and potassium (C) concentration. *P < 0.05 vs. LS. Data are individual values and means ± SD; n = 10 (5 males/5 females) mice/group.

Figure 2.

Group × sex comparisons in low-salt (LS) and high-salt (HS) diet-treated mice. Data were analyzed using two-way ANOVA with Sidak post hoc test to identify differences in plasma 8-isoprostane concentration. *P < 0.05 vs. LS. Data are individual values and means ± SD; n = 16 (8 males/8 females) mice/group. *P < 0.05 vs. LS.

Figure 3.

Group × time comparisons in low-salt (LS) and high-salt (HS) diet-treated mice. Data were analyzed using two-way mixed-model ANOVA with Sidak post hoc test to identify differences in systolic blood pressure (BP; A) and aortic pulse wave velocity (PWV; C). Data were analyzed using unpaired t test to identify differences in Δsystolic BP (B) and Δaortic PWV (D). *P < 0.05 vs. LS at 0, 2, 4, 6, 8, and 10 days. P < 0.05 vs. the corresponding week, respectively. Data are individual values and means ± SD; n = 12 (6 males/6 females) mice/group.

Figure 4.

Bivariate correlational analysis was used to determine the relationship between aortic pulse wave velocity (PWV) and systolic blood pressure (BP; A), as well as the relationship between change in systolic BP and aortic PWV (B) in low- and high-salt diet-treated mice.

Figure 5.

Group comparisons in low-salt (LS) and high-salt (HS) diet-treated mice. Data were analyzed using unpaired t test to identify differences in aortic lumen diameter (A), medial cross-sectional area (CSA; B), wall-to-lumen area (C), collagen (D), and elastin (E) content. Images are accompanied by representative images of collagen and elastin staining. Black scale bars are equal to 200 µm. *P < 0.05 vs. LS. Data are individual values and means ± SD; n = 12 (6 males/6 females) mice/group.

Figure 6.

Group × concentration comparisons in low-salt (LS) and high-salt (HS) diet-treated mice. Data were analyzed using two-way mixed model ANCOVA with Sidak post hoc test to identify differences in carotid artery vasodilation to acetylcholine (ACh; A). Data were analyzed using unpaired t test to identify differences in nitric oxide (NO)-mediated vasodilation (B) and half-maximal effective concentration (EC₅₀) to ACh (C). Data were analyzed using two-way mixed model ANCOVA with Sidak post hoc test to identify differences in carotid artery vasodilation to ACh in the presence of Tempol (D). Data were analyzed using unpaired t test to identify differences in NO-mediated vasodilation (E) and EC₅₀ to ACh (F) in the presence of Tempol. Data were analyzed using two-way mixed model ANCOVA with Sidak post hoc test to identify differences in carotid artery vasodilation to sodium nitroprusside (G). *P < 0.05 vs. LS response to ACh. †P < 0.05 vs. l-NAME response to ACh. Data are individual values and means ± SD; n = 10–14 (5–7 males/5–6 females) mice/group.

Figure 7.

Bivariate correlational analysis was used to determine relations between maximal vasodilation to acetylcholine with systolic blood pressure (BPl; A) or aortic pulse wave velocity (PWV; B), as well as relations between maximal vasodilation to sodium nitroprusside with systolic blood pressure (BP; C) or aortic pulse wave velocity (PWV; D) in low- and high-salt diet-treated mice.