Western diet-induced endothelial glycocalyx remodeling is partially reversed by fasting

Abstract

A Western diet (WD) that contains high fat and sugar content increases the risk of diabetes and diabetes-related vascular dysfunction. The endothelial glycocalyx is a gel-like structure bound to the vascular endothelium that is depleted in patients with diabetes and in preclinical models of diabetes. Glycocalyx depletion is believed to initiate vascular dysfunction. However, early glycocalyx adaptations prior to diabetes remain uncertain, as we have shown that glycocalyx thickness and integrity are increased, rather than depleted, 1 wk after initiating WD in mice. Despite greater glycocalyx properties, WD-fed mice still develop vascular dysfunction, suggesting that WD-induced glycocalyx remodeling may be a potential risk factor for diabetes-related vascular dysfunction. Therefore, we sought to determine the transient nature of WD-induced glycocalyx remodeling in response to a 6-h fast as a minimally intensive intervention. Glycocalyx properties were examined in nonfasted and 6-h fasted mice after 1 wk of control or WD consumption. Increased glycocalyx thickness in WD mice was abolished by fasting, whereas glycocalyx thickness was unaffected by fasting in control mice. Glycocalyx integrity was greater in WD compared with control mice but was unaffected by fasting in NC and WD mice. We observed no meaningful differences in microcirculatory hemodynamics between groups. Collectively, WD-induced glycocalyx thickening was rapidly reversed by fasting, providing insight into the transient nature of glycocalyx remodeling in response to a 6-h fast, suggesting that glycocalyx remodeling is one of the earliest and potentially modifiable vascular adaptations to WD, highlighting it as a potential target for future studies.NEW & NOTEWORTHY We observed greater glycocalyx thickness and integrity in mice fed a Western diet for 1 wk. A 6-h fast abolished differences in glycocalyx thickness between Western diet- and control diet-fed mice. However, glycocalyx integrity was unaffected by fasting, remaining greater in Western diet compared with control mice regardless of fasting status. These findings suggest that glycocalyx remodeling may be one of the earliest modifiable vascular adaptations to Western diet that is also partially reversible by fasting.

Keywords: cardiovascular disease; diabetes; microcirculation; prediabetes; vascular function.

Figure 1.

Comparison of non-fasted and fasted normal chow (NC) and Western diet (WD)-treated mice using one-way ANOVA to determine differences in body mass (A; n = 19–24 mice/group) and blood glucose (B; n = 19–24 mice/group). When a significant ANOVA was present, the two-stage step-up method of Benjamini, Krieger, and Yekutieli was used to identify group differences. *P<0.05 vs. non-fasted NC. †P<0.05 vs. non-fasted WD. Data are individual values (males = circles, females = triangles) and/or means±SEM.

Figure 2.

Comparison of non-fasted and fasted normal chow (NC) and Western diet (WD)-treated mice using one-way ANOVA to determine differences in glycocalyx thickness (A; n = 15–24 mice/group) and perfused boundary region (PBR; B; n = 19–24 mice/group). Two-way mixed model ANOVA was used to determine differences PBR in non-fasted NC vs. non-fasted WD (C; n = 24 mice/group), fasted NC vs. fasted WD (D; n = 19–20 mice/group), non-fasted NC vs. fasted NC (E; n = 20–24 mice/group), and non-fasted WD vs. fasted WD (F; n = 19–24 mice/group). When a significant ANOVA was present, the two-stage step-up method of Benjamini, Krieger, and Yekutieli was used to identify group differences. *P<0.05 vs. non-fasted NC. †P<0.05 vs. non-fasted WD. ‡P<0.05 vs. fasted NC. Data are individual values (males = circles, females = triangles) and/or means±SEM.

Figure 3.

Comparison of non-fasted and fasted normal chow (NC) and Western diet (WD)-treated mice using one-way ANOVA to determine differences in microvascular density (A; n = 19–24 mice/group) and capillary density (B; n = 19–24 mice/group). Two-way mixed model ANOVA was used to determine differences microvascular density in non-fasted NC vs. non-fasted WD (C; n = 24 mice/group), fasted NC vs. fasted WD (D; n = 19–20 mice/group), non-fasted NC vs. fasted NC (E; n = 20–24 mice/group), and non-fasted WD vs. fasted WD (F; n = 19–24 mice/group). When a significant ANOVA was present, the two-stage step-up method of Benjamini, Krieger, and Yekutieli was used to identify group differences. *P<0.05 vs. non-fasted NC. †P<0.05 vs. non-fasted WD. ‡P<0.05 vs. fasted NC. Data are individual values (males = circles, females = triangles) and/or means±SEM.

Figure 4.

Comparison of non-fasted and fasted normal chow (NC) and Western diet (WD)-treated mice using one-way ANOVA to determine differences in microvascular flow (A; n = 19–24 mice/group) and red blood cell (RBC) velocity (B; n = 19–24 mice/group). Two-way mixed model ANOVA was used to determine differences RBC velocity in non-fasted NC vs. non-fasted WD (C; n = 24 mice/group), fasted NC vs. fasted WD (D; n = 19–20 mice/group), non-fasted NC vs. fasted NC (E; n = 20–24 mice/group), and non-fasted WD vs. fasted WD (F; n = 19–24 mice/group). When a significant ANOVA was present, the two-stage step-up method of Benjamini, Krieger, and Yekutieli was used to identify group differences. *P<0.05 vs. non-fasted NC. †P<0.05 vs. non-fasted WD. Data are individual values (males = circles, females = triangles) and/or means±SEM.