Western diet (WD), characterized by excess saturated fat and sugar intake, is a major contributor to obesity and metabolic and arterial dysfunction in humans. However, these phenotypes are not consistently observed in traditional inbred, genetically identical mice. Therefore, we sought to determine the effects of WD on visceral adiposity and metabolic/arterial function in UM-HET3 mice, an outbred, genetically diverse strain of mice. Male and female UM-HET3 mice underwent normal chow (NC) or WD for 12 weeks. Body mass and visceral adiposity were higher in WD compared to NC (P < 0.05). Female WD mice had greater visceral adiposity than male WD mice (P < 0.05). The results of glucose and insulin tolerance tests demonstrated that metabolic function was lower in WD compared to NC mice (P < 0.05). Metabolic dysfunction in WD as was driven by male mice, as metabolic function in female WD mice was unchanged (P > 0.05). Systolic blood pressure (BP) and aortic stiffness were increased in WD after 2 weeks compared to baseline and continued to increase through week 12 (P < 0.05). Systolic BP and aortic stiffness were higher from weeks 2-12 in WD compared to NC (P < 0.05). Aortic collagen content was higher in WD compared to NC (P < 0.05). Carotid artery endothelium-dependent dilation was lower in WD compared to NC (P < 0.05). These data suggest sex-related differences in visceral adiposity and metabolic dysfunction in response to WD. Despite this, arterial dysfunction was similar in male and female WD mice, indicating this model may provide unique translational insight into similar sex-related observations in humans that consume WD.

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 weeks. Systolic BP and aortic stiffness, determined by pulse wave velocity (PWV), were increased in HS after 2 and 4 weeks, respectively, compared to 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 to LS mice (P<0.05). Aortic collagen content was ~81% higher in HS compared to LS (P<0.05), while aortic elastin content was similar between groups (P>0.05). Carotid artery endothelium‑dependent dilation (EDD) was ~10% lower in HS compared to LS (P<0.05), endothelium-independent dilation was similar between groups (P>0.05). Lastly, there was a strong relationship between systolic BP and PWV (r2=0.40, P<0.05), as well as inverse relationships 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 to humans that consume a HS diet.

One of the most important lifestyle factors that contributes to cardiovascular disease risk is excess dietary salt intake. In the US, ~90% of adults consume too much salt, and the average salt intake is ~2.3x higher than recommended by the American Heart Association. Excess salt consumption contributes to cardiovascular disease risk by elevating systolic blood pressure (BP) and inducing arterial dysfunction in humans. However, this arterial phenotype is not typically observed in inbred, genetically identical mouse strains that consume a high-salt (HS) diet, which may be due to strain-specific resistance to HS diet. Thus, we sought to determine the effects of HS diet consumption on systolic 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 (1% NaCl [LS]) or HS (4% NaCl) diet for 12 weeks. Systolic BP was increased after 2 weeks and aortic stiffness, determined by pulse wave velocity (PWV), was increased after 4 weeks in HS mice compared to baseline (P<0.05). Systolic BP and PWV continued to increase throughout the 12-week dietary intervention in HS mice (P<0.05), while systolic BP and PWV were unchanged in LS mice over the same timeframe (P>0.05). Histological analysis revealed that aortic collagen content was ~81% higher in HS compared to LS mice (P<0.05). Aortic elastin content, lumen diameter, medial wall-to-lumen ratio, and medial cross-sectional area were similar between groups (P>0.05). Endothelium‑dependent dilation (EDD), determine by carotid artery vasodilation to acetylcholine (ACh), was ~10% lower in HS compared to LS mice (P<0.05). In the presence of the nitric oxide (NO) synthase inhibitor, L-NAME, ACh-mediated dilation was blunted in HS and LS mice (P<0.05 vs ACh), but was similar between groups (P>0.05). There was a tendency for NO-mediated vasodilation, determined by subtracting ACh+L-NAME max vasodilation from ACh max vasodilation, to be higher in LS compared to HS mice (P=0.057). Endothelium-independent dilation (EID), determined by carotid artery vasodilation to sodium nitroprusside, was similar between groups (P>0.05). Lastly, there was a strong relationship between systolic BP and PWV (r2=0.40, P<0.05), as well as inverse relationships between EDD and systolic BP (r2=0.21, P<0.05) or PWV (r2=0.20, P<0.05). However, no relationship between systolic BP or aortic stiffness and EID was present (P>0.05). Lastly, we observed no sex-related difference in any measurement of arterial function (P>0.05 for all). Taken together, these findings provide evidence that a HS diet in UM-HET3 mice induces progressive elevations in systolic BP and aortic stiffness, which are accompanied by impaired EDD. These data suggest that outbred, genetically diverse mice may provide unique translational insight into HS diet-induced elevations in systolic BP and arterial dysfunction in humans living in industrialized societies. This study was funded in part by a grant from the National Institutes of Health (R00 AT010017). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

In recent years, UM-HET3 mice have become more commonly used in biomedical research. UM-HET3 mice are an outbred, genetically diverse strain of mice that is produced by crossing four inbred strains: BALB/cByJ, C57BL/6J, C3H/HeJ, and DBA/2J. Notably, the UM-HET3 strain is used by the National Institute on Aging Interventions Testing Program to investigate treatments that may extend lifespan and delay disease/dysfunction, while minimizing the impact of strain-specific phenotypes that might be observed in inbred, genetically identical strains like the C57BL/6J strain of mice. Here, we sought to examine phenotypic differences between age-matched male and female inbred, C57BL/6J and outbred, UM-HET3 mice (age: 6.4±0.0 mo, n=16 [8M/8F] per group). UM-HET3 had a greater body mass (C57BL/6J: 27±1 vs. UM-HET3: 32±1 g, P<0.05) and tibial length (C57BL/6J: 18.1±0.2 vs. UM-HET3: 19.6±0.3 mm, P<0.05) than C57BL/6J mice. Despite larger body stature, UM-HET3 mice had lower fasting blood glucose (C57BL/6J: 192±6 vs. UM-HET3: 168±5 mg/dL, P<0.05) and lower glucose area under the curve (AUC) in response to glucose tolerance testing (C57BL/6J: 34±1 vs. UM-HET3: 28±2 AU, P<0.05). On the contrary, there were no strain-related differences in glucose AUC in response to insulin tolerance testing (C57BL/6J: 14±1 vs. UM-HET3: 14±1 AU, P>0.05). We also observed no differences in systolic blood pressure (C57BL/6J: 115±2 vs. UM-HET3: 114±2 mmHg, P>0.05), although aortic stiffness, determined by pulse wave velocity (PWV), was lower in UM-HET3 compared to C57BL/6J mice (C57BL/6J: 309±5 vs. UM-HET3: 255±4 cm/sec, P<0.05). Endothelium-dependent dilation (EDD), determined by ex vivo maximal carotid artery dilation to acetylcholine (ACh), was lower in C57BL/6J compared to UM-HET3 (C57BL/6J: 84±2 vs. UM-HET3: 90±1%, P<0.05). In the presence of the nitric oxide (NO) synthase inhibitor, L-NAME, maximal dilation to ACh was similar between groups (C57BL/6J: 38±4 vs. UM-HET3: 34±4%, P>0.05). Thus, NO-mediated dilation, determined by subtracting ACh+L-NAME maximal dilation from ACh maximal dilation, was higher in UM-HET3 compared to C57BL/6J mice (C57BL/6J: 45±3 vs. UM-HET3: 57±4%, P<0.05). We observed no differences in endothelium-independent dilation, determined by ex vivo maximal dilation to sodium nitroprusside (C57BL/6J: 87±1 vs. UM-HET3: 90±2%, P>0.05). In summary, C57BL/6J mice appear to be smaller in stature, but with worse glucose handling, as indicated by impaired fasting glucose and glucose tolerance, compared to UM-HET3 mice. There are also strain differences in arterial function, as aortic stiffness was higher and EDD was lower in C57BL/6J compared to UM-HET3 mice. Strain differences in EDD appear to be due to a reduction in NO-mediated dilation in C57BL/6J mice. Collectively, these data suggest that there are phenotypic differences between these strains, indicating worse metabolic and arterial function in inbred, C57BL/6J compared to outbred, UM-HET3 mice. This study was funded in part by a grant from the National Institutes of Health (R00 AT010017). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.