Uncoupling of Ca2+ sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia

There are no treatments available for vascular dementia, the second-most common dementia syndrome, and patients decline rapidly after diagnosis. This syndrome is primarily due to hypertension and is associated with reduced cerebral blood flow (CBF). To explore this, we studied mechanisms of vascular dysfunction in pial arteries from hypertensive mice. These mice exhibit reduced CBF, hyperconstricted pial arteries, and behavior approximating human vascular dementia. Using myography, electrophysiology, and Ca 2+ imaging, we found that the increased constriction was due to separation of the sarcoplasmic reticulum from the plasma membrane in vascular smooth muscle cells, which prevented vasodilatory Ca 2+ signals from activating large-conductance K + channels. We propose that restoring this coupling could improve CBF and slow disease progression. The deficit in cerebral blood flow (CBF) seen in patients with hypertension-induced vascular dementia is increasingly viewed as a therapeutic target for disease-modifying therapy. Progress is limited, however, due to uncertainty surrounding the mechanisms through which elevated blood pressure reduces CBF. To investigate this, we used the BPH/2 mouse, a polygenic model of hypertension. At 8 mo of age, hypertensive mice exhibited reduced CBF and cognitive impairment, mimicking the human presentation of vascular dementia. Small cerebral resistance arteries that run across the surface of the brain (pial arteries) showed enhanced pressure-induced constriction due to diminished activity of large-conductance Ca 2+ -activated K + (BK) channels—key vasodilatory ion channels of cerebral vascular smooth muscle cells. Activation of BK channels by transient intracellular Ca 2+ signals from the sarcoplasmic reticulum (SR), termed Ca 2+ sparks, leads to hyperpolarization and vasodilation. Combining patch-clamp electrophysiology, high-speed confocal imaging, and proximity ligation assays, we demonstrated that this vasodilatory mechanism is uncoupled in hypertensive mice, an effect attributable to physical separation of the plasma membrane from the SR rather than altered properties of BK channels or Ca 2+ sparks, which remained intact. This pathogenic mechanism is responsible for the observed increase in constriction and can now be targeted as a possible avenue for restoring healthy CBF in vascular dementia.