Cerebral arteriolar and neurovascular dysfunction after chemically induced menopause in mice.

TitleCerebral arteriolar and neurovascular dysfunction after chemically induced menopause in mice.
Publication TypeJournal Article
Year of Publication2022
AuthorsBlackwell JA, Silva JF, Louis EM, Savu A, Largent-Milnes TM, Brooks HL, Pires PW
JournalAm J Physiol Heart Circ Physiol
Date Published2022 Nov 01
KeywordsAnimals, Arterioles, Cerebrovascular Disorders, Cholinergic Agents, Estrogens, Female, Hyperemia, Menopause, Mice, Nitric Oxide

Cognitive decline is linked to decreased cerebral blood flow, particularly in women after menopause. Impaired cerebrovascular function precedes the onset of dementia, possibly because of 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 Ca-activated K channels (BK) are the final effectors of several pathways responsible for functional hyperemia, and their expression is modulated by estrogen. However, it remains unknown whether BK 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 BK 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. BK function was significantly impaired in Meno compared with control, without changes in voltage-gated K channel activity. Cerebral functional hyperemia, measured by laser-speckle contrast imaging during whisker 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. Cerebral parenchymal arterioles from menopause mice showed increased myogenic tone. We identified an impairment in smooth muscle cell BK channel activity, without a reduction in endothelium-dependent dilation or nitric oxide production. Microvascular dysfunction was associated with a reduction in neurovascular responses after somatosensory stimulation. Despite the neurovascular impairment, cognitive abilities were maintained in menopausal mice.

Alternate JournalAm J Physiol Heart Circ Physiol
PubMed ID36149767
PubMed Central IDPMC9602916
Grant ListP30 DA051355 / DA / NIDA NIH HHS / United States
R01 AG073230 / AG / NIA NIH HHS / United States
R01 NS099292 / NS / NINDS NIH HHS / United States
R00 HL140106 / HL / NHLBI NIH HHS / United States
R01 HL131834 / HL / NHLBI NIH HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, PhD