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Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling

Pericytes are perivascular mural cells that enwrap brain capillaries and maintain blood-brain barrier (BBB) integrity. Most studies suggest that pericytes regulate cerebral blood flow (CBF) and oxygen delivery to activated brain structures, known as neurovascular coupling. While we have previously s...

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Autores principales: Kisler, Kassandra, Nikolakopoulou, Angeliki M., Sweeney, Melanie D., Lazic, Divna, Zhao, Zhen, Zlokovic, Berislav V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033444/
https://www.ncbi.nlm.nih.gov/pubmed/32116568
http://dx.doi.org/10.3389/fncel.2020.00027
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author Kisler, Kassandra
Nikolakopoulou, Angeliki M.
Sweeney, Melanie D.
Lazic, Divna
Zhao, Zhen
Zlokovic, Berislav V.
author_facet Kisler, Kassandra
Nikolakopoulou, Angeliki M.
Sweeney, Melanie D.
Lazic, Divna
Zhao, Zhen
Zlokovic, Berislav V.
author_sort Kisler, Kassandra
collection PubMed
description Pericytes are perivascular mural cells that enwrap brain capillaries and maintain blood-brain barrier (BBB) integrity. Most studies suggest that pericytes regulate cerebral blood flow (CBF) and oxygen delivery to activated brain structures, known as neurovascular coupling. While we have previously shown that congenital loss of pericytes leads over time to aberrant hemodynamic responses, the effects of acute global pericyte loss on neurovascular coupling have not been studied. To address this, we used our recently reported inducible pericyte-specific Cre mouse line crossed to iDTR mice carrying Cre-dependent human diphtheria toxin (DT) receptor, which upon DT treatment leads to acute pericyte ablation. As expected, DT led to rapid progressive loss of pericyte coverage of cortical capillaries up to 50% at 3 days post-DT, which correlated with approximately 50% reductions in stimulus-induced CBF responses measured with laser doppler flowmetry (LDF) and/or intrinsic optical signal (IOS) imaging. Endothelial response to acetylcholine, microvascular density, and neuronal evoked membrane potential responses remained, however, unchanged, as well as arteriolar smooth muscle cell (SMC) coverage and functional responses to adenosine, as we previously reported. Together, these data suggest that neurovascular uncoupling in this model is driven by pericyte loss, but not other vascular deficits or neuronal dysfunction. These results further support the role of pericytes in CBF regulation and may have implications for neurological conditions associated with rapid pericyte loss such as hypoperfusion and stroke, as well as conditions where the exact time course of global regional pericyte loss is less clear, such as Alzheimer’s disease (AD) and other neurogenerative disorders.
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spelling pubmed-70334442020-02-28 Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling Kisler, Kassandra Nikolakopoulou, Angeliki M. Sweeney, Melanie D. Lazic, Divna Zhao, Zhen Zlokovic, Berislav V. Front Cell Neurosci Cellular Neuroscience Pericytes are perivascular mural cells that enwrap brain capillaries and maintain blood-brain barrier (BBB) integrity. Most studies suggest that pericytes regulate cerebral blood flow (CBF) and oxygen delivery to activated brain structures, known as neurovascular coupling. While we have previously shown that congenital loss of pericytes leads over time to aberrant hemodynamic responses, the effects of acute global pericyte loss on neurovascular coupling have not been studied. To address this, we used our recently reported inducible pericyte-specific Cre mouse line crossed to iDTR mice carrying Cre-dependent human diphtheria toxin (DT) receptor, which upon DT treatment leads to acute pericyte ablation. As expected, DT led to rapid progressive loss of pericyte coverage of cortical capillaries up to 50% at 3 days post-DT, which correlated with approximately 50% reductions in stimulus-induced CBF responses measured with laser doppler flowmetry (LDF) and/or intrinsic optical signal (IOS) imaging. Endothelial response to acetylcholine, microvascular density, and neuronal evoked membrane potential responses remained, however, unchanged, as well as arteriolar smooth muscle cell (SMC) coverage and functional responses to adenosine, as we previously reported. Together, these data suggest that neurovascular uncoupling in this model is driven by pericyte loss, but not other vascular deficits or neuronal dysfunction. These results further support the role of pericytes in CBF regulation and may have implications for neurological conditions associated with rapid pericyte loss such as hypoperfusion and stroke, as well as conditions where the exact time course of global regional pericyte loss is less clear, such as Alzheimer’s disease (AD) and other neurogenerative disorders. Frontiers Media S.A. 2020-02-14 /pmc/articles/PMC7033444/ /pubmed/32116568 http://dx.doi.org/10.3389/fncel.2020.00027 Text en Copyright © 2020 Kisler, Nikolakopoulou, Sweeney, Lazic, Zhao and Zlokovic. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular Neuroscience
Kisler, Kassandra
Nikolakopoulou, Angeliki M.
Sweeney, Melanie D.
Lazic, Divna
Zhao, Zhen
Zlokovic, Berislav V.
Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling
title Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling
title_full Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling
title_fullStr Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling
title_full_unstemmed Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling
title_short Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling
title_sort acute ablation of cortical pericytes leads to rapid neurovascular uncoupling
topic Cellular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033444/
https://www.ncbi.nlm.nih.gov/pubmed/32116568
http://dx.doi.org/10.3389/fncel.2020.00027
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