Uncoupling of Ca 2+ sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia.

Jade L Taylor, Katy R Walsh, Ioana-Emilia Mosneag, Thea G E Danby, Nadim Luka, Bishal Chanda, Ingo Schiessl, Ross A Dunne, David Hill-Eubanks, Grant W Hennig, Stuart M Allan, Mark T Nelson, Adam S Greenstein, Harry A T Pritchard

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article numbere2307513120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number33
Early online date7 Aug 2023
Publication statusPublished - 15 Aug 2023


  • calcium imaging
  • dementia
  • hypertension
  • ion channels


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