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

Abstract

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 Ca2+-activated K+channels (BKCa) play an essential role in vasodilatory responses and maintenance of myogenic tone in resistance arteries. BKCacan 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 BKCafunction in cerebral arteries, as a consequence of nitro-oxidative stress, are associated with blunted neurovascular responses in the5x-FADmodel of AD. Using pressure myography, we observed that posterior communicating arteries (PComA) from 5 months-old female5x-FADmice showed higher spontaneous myogenic tone than wild-type (WT) littermates. Constriction to the BKCablocker iberiotoxin (30 ηM) was smaller in5x-FADthan WT, suggesting lower basal BKCaactivity, which was independent of alterations in intracellular Ca2+transients or BKCamRNA expression. These vascular changes were associated with higher levels of oxidative stress in female5x-FADand a higher level of S-nitrosylation in the BKCaα-subunit. In females, pre-incubation of PComA from5x-FADwith the reducing agent DTT (10 μM) rescued iberiotoxin-induced contraction. Female5x-FADmice showed increased expression of iNOS mRNA, lower resting cortical perfusion atop the frontal cortex, and impaired neurovascular coupling responses. No significant differences between male5x-FADand WT were observed for all parameters above. These data suggest that the exacerbation in BKCaS-nitrosylation contributes to cerebrovascular and neurovascular impairments in female5x-FADmice.