TY - JOUR
T1 - Uncoupling of Ca
2+ sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia.
AU - Taylor, Jade L
AU - Walsh, Katy R
AU - Mosneag, Ioana-Emilia
AU - Danby, Thea G E
AU - Luka, Nadim
AU - Chanda, Bishal
AU - Schiessl, Ingo
AU - Dunne, Ross A
AU - Hill-Eubanks, David
AU - Hennig, Grant W
AU - Allan, Stuart M
AU - Nelson, Mark T
AU - Greenstein, Adam S
AU - Pritchard, Harry A T
PY - 2023/8/15
Y1 - 2023/8/15
N2 - 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.
AB - 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.
KW - calcium imaging
KW - dementia
KW - hypertension
KW - ion channels
UR - http://www.scopus.com/inward/record.url?scp=85166784398&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/a36cc7d4-bbb6-3cf5-86e5-15ddbbe09eac/
U2 - 10.1073/pnas.2307513120
DO - 10.1073/pnas.2307513120
M3 - Article
C2 - 37549299
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 33
M1 - e2307513120
ER -