S-18-2: HYPERTENSION AS A DRIVER OF CEREBRAL SMALL VESSEL DISEASE AND DEMENTIA

Abstract

Hypertension is the principal cause of vascular dementia. Unfortunately however, lowering blood pressure after the onset of cognitive decline does not slow disease progression and currently, vascular dementia is a disease with no available treatment. A principal feature of hypertension-related vascular dementia is a reduction in cerebral blood flow. Precisely how elevated blood pressure reduces cerebral blood flow is unknown and to investigate this further we used a polygenic model of hypertension, the BPH/2 mouse. Aged 8 months, BPH/2 mice exhibited cognitive impairment mimicking the human presentation of vascular dementia and in addition, cerebral blood flow was reduced. Small cerebral resistance arteries which run across the surface of the brain (pial arteries) showed enhanced pressure-induced constriction due to lack of activity of large conductance Ca2+ activated K+ channels (BK channels), key vasodilatory ion channels of cerebral vascular smooth muscle cells. BK channels are activated by transient intracellular signals from the sarcoplasmic reticulum called Ca2+ sparks, leading to hyperpolarisation and vasodilation. Combining patch clamp electrophyiology, high speed confocal imaging and proximity ligation assays we demonstrated that while the biophysical properties of BK channels and Ca2+ sparks remained intact, physical separation of the plasma membrane from the sarcoplasmic reticulum uncoupled the vasodilatory mechanism. This novel pathogenic mechanism is responsible for the increased constriction and can be now targeted as a possible avenue to restore healthy cerebral blood flow in vascular dementia.