Cerebral Artery Function And Stiffness Is Dependent On Apoe Genotype And Ovariectomy Status In Mice

The major risk factors for late-onset Alzheimer’s Disease (LOAD) include old age, female sex and the APOE4 allele. Post-menopausal females with an APOE4 allele have higher rates of LOAD compared with age-matched males with an APOE4 allele, suggesting an interaction between APOE genotype and estrogen deficiency. Importantly, cerebrovascular dysfunction is a contributor to LOAD risk. However, it is unknown if APOE genotype and estrogen deficiency interact to impact cerebrovascular function.Young female homozygous APOE3 and APOE4 mice (n=4-6 per group; ~6 months old) fed a high-fat, high-cholesterol diet were intact (sham) or ovariectomized (OVX). We assessed endothelium-dependent dilation to increasing doses of acetylcholine (ACh) in pressurized posterior cerebral arteries (PCAs). There was an interaction effect of APOE genotype and OVX status for endothelium-dependent dilation (p=0.03), such that APOE3 -Sham mice had a greater endothelium-dependent dilation compared to the APOE3 -OVX group (70±9.1% vs. 39±7.6%, p=0.003). These differences were mediated by nitric oxide as indicated by the absence of dilation in the presence of N omega-Nitro-L-arginine methyl ester hydrocholoride (L-NAME, Sham: 3.7±3.3% vs OVX: 4.1±4.0%, p= 0.99). In contrast, APOE4 -OVX had preserved endothelium-dependent dilation compared with APOE4 -Sham (49.9±14.8% vs 56.1±9.2%, p=0.8). Endothelium-independent dilation was assessed by the response to increasing doses of sodium nitroprusside and did not differ among groups (all p>0.05). Passive stiffness was measured in isolated PCAs after incubation in a calcium-free solution. For the elastic modulus at low pressures, there was an interaction effect of APOE genotype and OVX status (p=0.03), with APOE4 -OVX having a higher elastic modulus compared to APOE4 -Sham (0.93±0.3 vs. 0.47±0.1, p=0.03). The elastic modulus was similar in APOE3 groups (sham: 0.64±0.01, OVX: 0.62±0.09, p=0.99). Overall, we found that estrogen deficiency impacts cerebral artery endothelial function in APOE3 , but not APO E4 mice, while estrogen deficiency impacts cerebral artery stiffness in APOE4 , but not APOE3 mice. These results shed light on the impact of APOE genotype on the cerebral vasculature, suggesting a potential mechanism for LOAD.