Sex and age modulate the impact of large artery stiffness on cerebrovascular function and neuroinflammation

Introduction: Large artery stiffness (LAS) is a characteristic of vascular aging that has adverse effects on multiple target organs, notably the brain. Increased systemic pulse pressure from LAS contributes to cerebrovascular dysfunction, neuroinflammation, and cognitive impairment. While we know acute exposure to LAS causes cerebral artery dysfunction, the long-term effects of LAS have yet to be investigated. Previous studies have not examined the impact of sex on the cerebrovascular dysfunction caused by LAS. The objective of this study was to investigate sex differences in the effects of short- and long-term exposure to LAS on cerebrovascular and cognitive function. We hypothesized that old Eln+/- mice would have greater cerebrovascular dysfunction, neuroinflammation, and cognitive impairment compared to old Eln+/+ mice, and young Eln+/+ and Eln+/- mice. We also hypothesized that female mice would have greater cerebrovascular dysfunction, neuroinflammation, and cognitive impairment compared to age-matched males. Methods: We used a model of increased LAS, mice haploinsufficient for the elastin gene (Eln +/-), compared with wildtype (Eln +/+) mice. We studied male and female mice, at both young (6 months) and old (24 months) ages. We measured endothelium-dependent dilation ex vivo in pre-constricted, pressurized posterior cerebral arteries (PCAs) by the maximal response to acetylcholine (ACh). We also quantified cerebral cortex and artery gene expression of inflammatory and oxidative stress-related genes using RT-qPCR. Lastly, we used rotarod and nest building assessments to measure cognitive impairment. Whole group comparisons, as well as sex-specific comparisons, were made for age and genotype using a 2-way ANOVA. A p<0.05 was considered statistically significant. Data are mean±SD. Results: In males, percent maximum dilation to ACh was lower in old Eln+/+ compared to young Eln+/+ (p<0.001), but there was no age-related difference in Eln+/- mice (p=0.19). The opposite occurs in females, where dilation to ACh is lower in old Eln+/- compared to young Eln+/- (p<0.001), but similar with age in Eln+/+ mice (p=0.07). In the cortex, expression of both superoxide dismutase (SOD) 1 and 3 were lower in old Eln+/- mice compared to old Eln+/+ (p<0.001, p=0.04). Additionally, in cerebral arteries, SOD3 was lower in old Eln+/- compared to old Eln+/+ (p=0.04). Lastly, rotarod time (p<0.001) and nest building scores (p=0.006) were lower with age, with no genotype effect (p>0.05). Conclusion: These data suggest long-term exposure to LAS impairs cerebral artery endothelial function particularly in females, and weakens antioxidant defenses in the cerebral arteries and brain. These results indicate that the adverse effects of long-term LAS may be more prominent in females. Funded by AARG-200675709, TL1TR002371. This abstract was presented at the American Physiology Summit 2025 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.