Cerebral arteriolar and neurovascular dysfunction after chemically induced menopause in mice

Jade A. Blackwell, Josiane F. Silva, Emma M. Louis, Andrea Savu, Tally M. Largent-Milnes, Heddwen L. Brooks, Paulo W. Pires

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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 Ca2 þ -activated K þ channels (BKCa) are the final effectors of several pathways responsible for functional hyperemia, and their expression is modulated by estrogen. However, it remains unknown whether 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 with control, without changes in voltage-gated K þ 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.

Original languageEnglish (US)
Pages (from-to)H845-H860
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume323
Issue number5
DOIs
StatePublished - Nov 2022

Keywords

  • BK channels
  • cerebral functional hyperemia
  • cerebral parenchymal arterioles
  • menopause
  • myogenic tone

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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