Sex has a greater influence on cerebral perfusion than large artery stiffness in middle-aged mice
Authors: Cullen Abigail , Reeve Emily , Henson Grant , Pike Martin , Woltjer Randy , Walker Ashley 
Published: May 2023

Females and individuals with greater large artery stiffness are at higher risk for developing cognitive impairment. Lower cerebral perfusion and vasoreactivity are associated with cognitive impairment, but it is unknown if sex and arterial stiffness interact to affect these. We hypothesized that sex and chronic exposure to stiffer large arteries, modeled by elastin haploinsufficiency, would interact to cause impaired cerebral perfusion and vasoreactivity in middle-aged mice. We studied male and female (15 months, n=18, 17) elastin wildtype (Eln+/+) and elastin haploinsufficient (Eln+/-) mice (n=20,15). Cerebral perfusion was obtained in anesthetized mice by arterial spin labeling MRI under basal (100% O2) and hypercapnic (95/5% O2/CO2) conditions, employing an 11.75T Bruker-Biospin Animal MRI system. Perfusion was analyzed using both Paravision (Bruker) and Jim9 MRI analysis software (Xinapse Systems). Microglia were identified in paraffin-embedded brain sections by immunohistochemical staining for Iba1. Data were analyzed by a 2-way (sex x genotype) ANOVA. Data are mean±SEM. Females had lower perfusion during basal conditions in the thalamus (97.1±6.9 vs 116.4±6.4 mL/100g/min, p=0.023) and the cortex (81.7±5.7 vs 101.5±4.6 mL/100g/min, p=0.005) compared with males. Females also had lower perfusion during hypercapnia in the thalamus (76.7±9.7 vs 150.1±6.3 mL/100g/min, p <0.0001) and the cortex (96.1±5.3 vs 111.8±5.1 mL/100g/min, p=0.02) compared with males. There were no sex differences for cerebral perfusion in the hippocampal region. Elastin haploinsufficiency did not influence perfusion of any brain region during basal or hypercapnic conditions (all p>0.05). However, Eln+/- mice had a greater percent increase in perfusion to hypercapnia in the cortex (21.0±2.6 vs 13.9±1.7%, p=0.011) compared with Eln+/+ mice, and there were similar trends in the hippocampus (p=0.07) and thalamus (p=0.08). There was no interaction of sex and genotype on any outcome (all p>0.05). Iba1 staining of the cortex, but not the hippocampus or thalamus, indicated that Eln+/- mice (n=7) had more microglia content compared with Eln+/+ mice (n=12, 0.5±0.1 vs 0.3±0.1 % area, p=0.03). There was no effect of sex for microglia in any brain region (all p>0.05). Our results indicate that sex has a greater influence on cerebral perfusion than chronic exposure to large artery stiffness in middle-aged mice. However, genotype more significantly influences the cerebral vasoreactivity to hypercapnia compared with sex, potentially explained by the increased microglia content within the cortex. Female mice have lower cerebral perfusion than male mice in middle age, and this increases the risk for cognitive decline. This project was funded by R01 AG064016 and the Oregon Alzheimer's Tax Checkoff Fund. 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.