1. Sex-specific mechanisms of cerebral microvascular BK Ca dysfunction in a mouse model of Alzheimer's disease.
- Author
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da Silva JF, Polk FD, Martin PE, Thai SH, Savu A, Gonzales M, Kath AM, Gee MT, and Pires PW
- Abstract
Background: Cerebral microvascular dysfunction and nitro-oxidative stress are present in patients with Alzheimer's disease (AD) and may contribute to disease progression and severity. Large conductance Ca
2+ -activated K+ channels (BKCa ) play an essential role in vasodilatory responses and maintenance of myogenic tone in resistance arteries. BKCa impairment can lead to microvascular dysfunction and hemodynamic deficits in the brain. We hypothesized that reduced BKCa function in cerebral arteries mediates microvascular and neurovascular responses in the 5x-FAD model of AD., Methods: BKCa activity in the cerebral microcirculation was assessed by patch clamp electrophysiology and pressure myography, in situ Ca2+ sparks by spinning disk confocal microscopy, hemodynamics by laser speckle contrast imaging. Molecular and biochemical analyses were conducted by affinity-purification assays, qPCR, Western blots and immunofluorescence., Results: We observed that pial arteries from 5-6 months-old male and female 5x-FAD mice exhibited a hyper-contractile phenotype than wild-type (WT) littermates, which was linked to lower vascular BKCa activity and reduced open probability. In males, BKCa dysfunction is likely a consequence of an observed lower expression of the pore-forming subunit BKα and blunted frequency of Ca2+ sparks, which are required for BKCa activity. However, in females, impaired BKCa function is, in part, a consequence of reversible nitro-oxidative changes in the BKα subunit, which reduces its open probability and regulation of vascular tone. We further show that BKCa function is involved in neurovascular coupling in mice, and its dysfunction is linked to neurovascular dysfunction in the model., Conclusion: These data highlight the central role played by BKCa in cerebral microvascular and neurovascular regulation, as well as sex-dependent mechanisms underlying its dysfunction in a mouse model of AD.- Published
- 2024
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