Cargando…

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

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 reduce...

Descripción completa

Detalles Bibliográficos
Autores principales: Taylor, Jade L., Walsh, Katy R., Mosneag, Ioana-Emilia, Danby, Thea G. E., Luka, Nadim, Chanda, Bishal, Schiessl, Ingo, Dunne, Ross A., Hill-Eubanks, David, Hennig, Grant W., Allan, Stuart M., Nelson, Mark T., Greenstein, Adam S., Pritchard, Harry A. T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10433456/
https://www.ncbi.nlm.nih.gov/pubmed/37549299
http://dx.doi.org/10.1073/pnas.2307513120
_version_ 1785091651356590080
author Taylor, Jade L.
Walsh, Katy R.
Mosneag, Ioana-Emilia
Danby, Thea G. E.
Luka, Nadim
Chanda, Bishal
Schiessl, Ingo
Dunne, Ross A.
Hill-Eubanks, David
Hennig, Grant W.
Allan, Stuart M.
Nelson, Mark T.
Greenstein, Adam S.
Pritchard, Harry A. T.
author_facet Taylor, Jade L.
Walsh, Katy R.
Mosneag, Ioana-Emilia
Danby, Thea G. E.
Luka, Nadim
Chanda, Bishal
Schiessl, Ingo
Dunne, Ross A.
Hill-Eubanks, David
Hennig, Grant W.
Allan, Stuart M.
Nelson, Mark T.
Greenstein, Adam S.
Pritchard, Harry A. T.
author_sort Taylor, Jade L.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-10433456
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-104334562023-08-18 Uncoupling of Ca(2+) sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia Taylor, Jade L. Walsh, Katy R. Mosneag, Ioana-Emilia Danby, Thea G. E. Luka, Nadim Chanda, Bishal Schiessl, Ingo Dunne, Ross A. Hill-Eubanks, David Hennig, Grant W. Allan, Stuart M. Nelson, Mark T. Greenstein, Adam S. Pritchard, Harry A. T. Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2023-08-07 2023-08-15 /pmc/articles/PMC10433456/ /pubmed/37549299 http://dx.doi.org/10.1073/pnas.2307513120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Taylor, Jade L.
Walsh, Katy R.
Mosneag, Ioana-Emilia
Danby, Thea G. E.
Luka, Nadim
Chanda, Bishal
Schiessl, Ingo
Dunne, Ross A.
Hill-Eubanks, David
Hennig, Grant W.
Allan, Stuart M.
Nelson, Mark T.
Greenstein, Adam S.
Pritchard, Harry A. T.
Uncoupling of Ca(2+) sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia
title Uncoupling of Ca(2+) sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia
title_full Uncoupling of Ca(2+) sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia
title_fullStr Uncoupling of Ca(2+) sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia
title_full_unstemmed Uncoupling of Ca(2+) sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia
title_short Uncoupling of Ca(2+) sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia
title_sort uncoupling of ca(2+) sparks from bk channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10433456/
https://www.ncbi.nlm.nih.gov/pubmed/37549299
http://dx.doi.org/10.1073/pnas.2307513120
work_keys_str_mv AT taylorjadel uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia
AT walshkatyr uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia
AT mosneagioanaemilia uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia
AT danbytheage uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia
AT lukanadim uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia
AT chandabishal uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia
AT schiesslingo uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia
AT dunnerossa uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia
AT hilleubanksdavid uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia
AT henniggrantw uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia
AT allanstuartm uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia
AT nelsonmarkt uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia
AT greensteinadams uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia
AT pritchardharryat uncouplingofca2sparksfrombkchannelsincerebralarteriesunderlieshypoperfusioninhypertensioninducedvasculardementia