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...
Autores principales: | , , , , , , , , , , , , , |
---|---|
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 |