APOE4 negates the effects of ovarian hormones on cerebrovascular endothelial and mitochondrial function

The APOEε4 allele and oestrogen deficiency independently predispose females to an increased risk of vascular and metabolic impairments, but their cerebrovascular effects are less understood. The purpose of this study was to determine the interaction between APOE genotype and oestrogen on cerebrovascular endothelial and mitochondrial function. We studied young female homozygous APOEε3 and APOEε4 mice (n = 19-20/group; ∼6 months old) that were fed a high-fat diet and were ovariectomized (OVX), OVX and supplemented with 17β-oestradiol, or left intact. In APOEε3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilatation, which was rescued by 17β-oestradiol. However, in APOEε4 mice, there was no effect of OVX or 17β-oestradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17β-oestradiol treatment in APOEε3 mice, but there was no impact of OVX or 17β-oestradiol in the APOEε4 mice. In cerebral arteries and arterioles, 17β-oestradiol led to higher mitochondrial complex I respiration in APOEε3 but not APOEε4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes and pro-inflammatory factors. Overall these results indicate that the APOE genotype modulates the impact of OVX and oestradiol on the cerebral vasculature. We found that 17β-oestradiol enhances cerebrovascular endothelial and mitochondrial function in OVX APOEε3 mice but not in APOEε4 mice. This suggests that 17β-oestradiol supplementation may have more cerebrovascular benefits for APOEε4 non-carriers. KEY POINTS: Females have twice the risk of Alzheimer's disease than males, and the APOEε4 genetic variant has a greater risk for Alzheimer's disease than the APOEε3 variant. The risk for Alzheimer's disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. There are highly inconsistent results among past studies examining the interaction between APOE genotype and oestrogens on brain outcomes, and their impact on the vasculature has not been studied. We aimed to determine the impact of APOEε4 genotype on the cerebrovascular response to ovariectomy and oestradiol. We found that oestradiol improved cerebral artery endothelial function and mitochondrial respiration in ovariectomized APOEε3 mice following ovariectomy. In contrast APOEε4 mice were resistant to the beneficial effects of ovarian hormones on cerebrovascular and mitochondrial function. This research suggests that APOE genotype may be a consideration when weighing the risks and benefits of prescribing hormone replacement therapy to postmenopausal females.