Cerebral arteriolar and neurovascular dysfunction after chemically induced menopause in mice

Abstract

Cognitive decline is linked to decreased cerebral blood flow, particularly in women after menopause. Impaired cerebrovascular function precedes the onset of dementia, possibly due to reduced functional dilation in parenchymal arterioles. These vessels are bottlenecks of the cerebral microcirculation, and dysfunction can limit functional hyperemia in the brain. Large conductance Ca2+-activated K+ channels (BKCa) are the final effectors of several pathways responsible for functional hyperemia, and their expression is modulated by estrogen. However, it remains unknown if BKCa function is altered in cerebral parenchymal arterioles after menopause. Using a chemically-induced model of menopause, the 4-vinylcyclohexene diepoxide (VCD) model, which depletes follicles while maintaining intact ovaries, we hypothesized that menopause would be associated with reduced functional vasodilatory responses in cerebral parenchymal arterioles of wild-type mice via reduced BKCa function. Using pressure myography of isolated parenchymal arterioles, we observed that menopause (Meno) induced a significant increase in spontaneous myogenic tone. Endothelial function, assessed as nitric oxide production and dilation after cholinergic stimulation or endothelium-dependent hyperpolarization pathways, was unaffected by Meno. BKCa function was significantly impaired in Meno compared to Control, without changes in voltage-gated K+ channel activity. Cerebral functional hyperemia, measured by laser speckle contrast imaging during whiskers stimulation, was significantly blunted in Meno mice, without detectable changes in basal perfusion. However, behavioral testing identified no change in cognition. These findings suggest that menopause induces cerebral microvascular and neurovascular deficits.

Sex-specific mechanisms of cerebral microvascular BKCadysfunction in a mouse model of Alzheimer’s disease

“…Further, both females and males 5x-FAD mice showed a reduction in neurovascular responses during somatosensory stimulation. A similar neurovascular impairment was recently reported by us, in which female mice that underwent chemically-induced menopause showed reduced functional hyperemia responses associated with cerebral microvascular BK Ca impairment 41 . However, it is important to note that these studies, and our data presented herein, are associative, and further experiments are needed to definitively show the role of cerebral microvascular BK Ca in neurovascular coupling responses.…”

“…Impairment in BK Ca function is associated with vascular dysfunction in various disease models, including diabetes 48,49 , hypertension 50,51 , menopause 41,52 , cigarette smoking 53 and AD 28 . One limitation of the aforementioned studies is that they were all performed in a single sex, and the vast majority in males (with the exception of studies focused on menopause).…”

Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort

“…This observation was seen at a younger age, with lower CBF observed in older age [65,66]. HRT use in early menopause has been shown to improve peripheral vascular function [67], and in a recent study, estrogen use was associated with reduced cerebral vessels' smooth muscle tone in a menopausal mouse model [68]. It is possible that a ated effect on CBF in APOE4 could in part underpin the impact on brain volume and associated improved memory, which is worthy of future investigation.…”

Menopause causes metabolic and cognitive impairments in a chronic cerebral hypoperfusion model of vascular contributions to cognitive impairment and dementia

“…VCID alone led to impairments in spatial memory (Barnes maze) while menopause in VCID mice led to additional impairments in episodic-like memory (NOR) and activities of daily living (nest building). Others have examined cognitive effects of the accelerated ovarian failure model of menopause at baseline and have found no deficits [ 34 ]. While others have examined the cognitive effects of an OVX model of menopause, we are the first to examine the cognitive impact of this more clinically relevant menopause model on cognitive impairment in VCID.…”

“…This well characterized model leads to permanent acyclicity in rodents with few side effects [ 32 , 33 ]. Recent elegant work by Blackwell et al, using this accelerated ovarian failure model of menopause, showed that menopause impairs cerebrovascular function [ 34 ]. The effects of menopause in the context of VCID or underlying vascular pathology had yet to be examined.…”