Addition of high-sodium to Western diet induces additive arterial dysfunction despite an apparently healthy endothelial glycocalyx

Introduction: Western diet (WD) that is high in fat, sugar, and sodium content causes elevated blood pressure (BP) and vascular dysfunction, which leads to cardiovascular disease (CVD). While WDs used in preclinical studies are high in fat and sugar, their sodium content is often low, which limits their translations to humans. We have recently demonstrated that a low-sodium WD (LSWD) impairs vascular function, while augmenting microcirculatory function in mice. In contrast, a high-sodium NC (HSNC) diet impairs both vascular and microcirculatory function. Interestingly, a combined high-sodium WD (HSWD) demonstrates distinct microcirculatory adaptations of both LSWD and HSNC diets, although it is unclear how vascular function is affected by a HSWD. Here, we sought to determine the effects of HSWD on vascular function in mice. Method: 3 mo old male and female UM-HET3 mice were randomized into 1 of 4 diets for 12 weeks: LSNC (LabDiet #5001; 1.0% NaCl), HSNC (LabDiet #5G21; 4.0% NaCl), LSWD (LabDiet #5TJN; 0.4% NaCl), or HSWD (LabDiet #5GDL; 4.0% NaCl). Results: At week 12, body mass (LSNC: 30.8±4.6; HSNC: 31.1±5.4; LSWD: 44.8±6.5; HSWD:42.6±6.9 g) and non-fasting blood glucose (LSNC: 165±16; HSNC: 168±13; LSWD: 181±24; HSWD: 184±23 mg/dL) were higher in LSWD or HSWD, compared to LSNC and HSNC mice (P< 0.05). Systolic BP, measured by tail-cuff plethysmography, was similar between groups at baseline (P >0.05). Compared to LSNC, systolic BP was ~5-17% higher in weeks 2-12 in HSNC, LSWD, and HSWD (P< 0.05). From weeks 8-12, systolic BP was ~2-5% higher in HSWD compared to HSNC and LSWD (P< 0.05). Aortic stiffness, measured by aortic pulse wave velocity (PWV), was similar between groups at baseline (P >0.05). Compared to LSNC, aortic PWV was ~8-55% higher in weeks 2-12 in HSNC, LSWD, and HSWD (P< 0.05). From weeks 8-12, aortic PWV was ~ 6-22% higher in HSWD compared to HSNC and LSWD (P< 0.05). Endothelium-dependent dilation (EDD), measured by maximal vasodilation to acetylcholine in isolated pressurized carotid arteries, was lower in HSNC (84±2%), LSWD (81±2%), and HSWD (73±4%), compared to NC (89±1%; P< 0.05). EDD was also lower in HSWD compared to HSNC and LSWD mice (P< 0.05). Endothelium-independent dilation (EID), measured by maximal vasodilation to sodium nitroprusside in isolated pressurized carotid arteries was similar between groups (LSNC: 90±1, HSNC: 90±1, LSWD: 88±2, HSWD: 86±2 %; P >0.05). Glycocalyx thickness, measured by intravital microscopy, was lower in HSNC (0.36±0.04 µm; P< 0.05), higher in LSWD (0.61±0.03 µm; P< 0.05), and similar in HSWD (0.50±0.05 µm; P >0.05) compared to LSNC (0.48±0.02 µm) mice. Perfused boundary region (inversely related to glycocalyx integrity), was higher in HSNC (2.34±0.05 µm; P< 0.05) and lower in LSWD (1.96±0.05 µm; P< 0.05) and HSWD (1.93±0.05 µm; P >0.05) compared to LSNC (2.19±0.04 µm) mice. Discussion: In summary, HSWD results in markedly worse vascular function as indicated by greater systolic BP and aortic stiffness and lower EDD than HSNC or LSWD alone, demonstrating an additive effect of HSWD on vascular dysfunction. Vascular dysfunction in HSWD was present despite an apparently healthy glycocalyx similar to LSWD. We also observed a slight but significant elevation in blood glucose in LSWD and HSWD mice, which may promote glycocalyx synthesis and could be an early adaptation in prediabetes. Taken together, our findings provide preliminary evidence for the additively detrimental effects of HSWD on vascular function despite an apparently healthy glycocalyx. Considering the vast majority of humans consuming WD that contains HS, incorporating a HSWD into preclinical studies is a practical, but often overlooked approach to enhance the translatability of the findings. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.