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 (BK Ca ) play an essential role in vasodilatory responses and maintenance of myogenic tone in resistance arteries. BK Ca can be modified in a pro-nitro-oxidative environment, resulting in decreased activity and vascular hyper-contractility, which can compromise cerebral blood flow regulation. We hypothesized that reductions in BK Ca function in cerebral arteries, as a consequence of nitro-oxidative stress, are associated with blunted neurovascular responses in the 5x-FAD model of AD. Using pressure myography, we observed that posterior communicating arteries (PComA) from 5 months-old female 5x-FAD mice showed higher spontaneous myogenic tone than wild-type (WT) littermates. Constriction to the BK Ca blocker iberiotoxin (30 nM) was smaller in 5x-FAD than WT, suggesting lower basal BK Ca activity, which was independent of alterations in intracellular Ca 2+ transients or BK Ca mRNA expression. These vascular changes were associated with higher levels of oxidative stress in female 5x-FAD and a higher level of S-nitrosylation in the BK Ca α-subunit. In females, pre-incubation of PComA from 5x-FAD with the reducing agent DTT (10 µM) rescued iberiotoxin-induced contraction. Female 5x-FAD mice showed increased expression of iNOS mRNA, lower resting cortical perfusion atop the frontal cortex, and impaired neurovascular coupling responses. No significant differences between male 5x-FAD and WT were observed for all parameters above. These data suggest that the exacerbation in BK Ca S-nitrosylation contributes to cerebrovascular and neurovascular impairments in female 5x-FAD mice.
Significance statement: Cerebral vascular dysfunction is increasingly recognized as a hallmark of Alzheimer's disease and other dementias. Impaired microvascular regulation can lead to deficits in blood flow to the brain. An intrinsic property of the resistance vasculature is to constrict when pressurized (myogenic tone), generating a vasodilatory reserve. Detrimental over-constriction is prevented by vascular feedback mechanisms, including the opening of large-conductance Ca 2+ -activated K + channels (BK Ca ). Here, using a combination of molecular biology tools with ex vivo and in vivo vascular assessments, we show a novel mechanism associated with BK Ca dysfunction in the cerebral microvasculature of female 5x-FAD mice. We report increased BK Ca S-nitrosylation linked to reduced activity and, consequently, higher basal myogenic tone. These changes were associated with lower perfusion of the frontal cortex and impaired neurovascular reactivity, suggesting that nitro-oxidative stress is an important mechanism of vascular dysfunction in Alzheimer's disease.