High-Sodium Diet Induces Vascular Dysfunction and Glycocalyx Depletion in UM-HET3 but Not C57BL/6J Mice

Excess dietary sodium causes hypertension and vascular dysfunction and is a risk factor for cardiovascular disease (CVD). To identify mechanisms by which a high-sodium (HS) diet increases CVD risk, preclinical studies have examined blood pressure (BP) and vascular function in HS diet-fed mice, typically inbred C57BL/6 mice. However, it has been suggested that C57BL/6 mice are resistant to HS diet-induced hypertension. Indeed, a recent meta-analysis identified a marginal elevation in BP in HS diet-fed C57BL/6 mice. We recently demonstrated that outbred UM-HET3 mice exhibit significant elevations in BP and vascular dysfunction that are accompanied by a depleted glycocalyx in response to HS diet. The glycocalyx is a negatively charged, gel-like protective layer on endothelium that contributes to endothelial function. Here, we examined BP and vascular function in C57BL/6J and UM-HET3 mice after 12 weeks of low-sodium (LS; 1% NaCl) or HS (4%NaCl) diets. We hypothesized that HS diet-fed UM-HET3 mice would demonstrate greater elevations in BP and vascular dysfunction than LS diet-fed UM-HET3 mice, and that we would observe minimal differences in BP and vascular function between LS- and HS-fed C57BL/6J mice. Systolic BP, measured by tail-cuff plethysmography, did not differ between strains at baseline (P >0.05). After 12 weeks of HS diet, UM-HET3 mice exhibited ~10-14% greater systolic BP compared to LS-fed UM-HET3 mice, LS-fed C57BL/6J mice, and HS-fed C57BL/6J mice (P< 0.05). Systolic BP was similar between LS- and HS-fed C57BL/6J mice (P >0.05). Aortic stiffness, measured by pulse wave velocity (PWV), was ~14% greater in C57BL/6J compared to UM-HET3 mice at baseline (P< 0.05). After 12 weeks of HS diet, UM-HET3 mice exhibited ~26% greater aortic PWV compared to LS-fed UM-HET3 mice and ~4-6% greater aortic PWV than LS- and HS-fed C57BL/6J mice (P< 0.05). Aortic PWV was similar between LS- and HS-fed C57BL/6J mice (P >0.05). Aortic collagen content was similar between strains (P >0.05), although HS-fed mice had ~20-54% greater collagen content than LS-fed mice (P< 0.05). In contrast, UM-HET3 mice exhibited ~41-59% greater aortic elastin content than C57BL/6J mice (P< 0.05), while elastin content was similar between LS and HS diets within strains (P >0.05). Endothelium-dependent dilation (EDD), measured by ex vivo maximal carotid artery dilation to acetylcholine, was ~9-12% greater in LS-fed UM-HET3 mice compared to HS-fed UM-HET3 mice, LS-fed C57BL/6J mice, and HS-fed C57BL/6J mice (P< 0.05). EDD was similar between LS- and HS-fed C57BL/6J mice (P >0.05). Endothelium-independent dilation, measured by maximal dilation to sodium nitroprusside, was similar between groups (P >0.05). Glycocalyx barrier function and glycocalyx thickness, measured via intravital microscopy in the mesenteric microcirculation, were ~7–8% and ~24-28% greater, respectively, in LS-fed UM-HET3 mice compared to HS-fed UM-HET3, and LS- and HS-fed C57BL/6J mice (P< 0.05). Glycocalyx barrier function and glycocalyx thickness were similar between LS- and HS-fed C57BL/6J mice (P >0.05). These findings demonstrate that UM-HET3 demonstrates significant vascular dysfunction in response to an HS diet, while C57BL/6J mice demonstrate marginal or no deficits in vascular function. One explanation is that C57BL/6J mice have pre-existing vascular dysfunction, demonstrated by greater aortic stiffness, lower aortic elastin content, lower EDD, and impaired glycocalyx properties in LS-fed C57BL/6J mice compared to LS-fed UM-HET3 mice. Taken together, these findings suggest that UM-HET3 mice may be a more relevant preclinical model of human HS diet-induced vascular dysfunction than C57BL/6J mice. 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.