TY  - JOUR
AU  - Kisler, Kassandra
AU  - Nikolakopoulou, Angeliki M.
AU  - Sweeney, Melanie D.
AU  - Lazić, Divna
AU  - Zhao, Zhen
AU  - Zloković, Berislav V.
PY  - 2020
UR  - https://www.frontiersin.org/article/10.3389/fncel.2020.00027/full
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3663
AB  - 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.
PB  - Frontiers Media SA
T2  - Frontiers in Cellular Neuroscience
T1  - Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling
VL  - 14
DO  - 10.3389/fncel.2020.00027
SP  - 27
ER  - 

@article{
author = "Kisler, Kassandra and Nikolakopoulou, Angeliki M. and Sweeney, Melanie D. and Lazić, Divna and Zhao, Zhen and Zloković, Berislav V.",
year = "2020",
abstract = "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.",
publisher = "Frontiers Media SA",
journal = "Frontiers in Cellular Neuroscience",
title = "Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling",
volume = "14",
doi = "10.3389/fncel.2020.00027",
pages = "27"
}

Kisler, K., Nikolakopoulou, A. M., Sweeney, M. D., Lazić, D., Zhao, Z.,& Zloković, B. V.. (2020). Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling. in Frontiers in Cellular Neuroscience
Frontiers Media SA., 14, 27.
https://doi.org/10.3389/fncel.2020.00027

Kisler K, Nikolakopoulou AM, Sweeney MD, Lazić D, Zhao Z, Zloković BV. Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling. in Frontiers in Cellular Neuroscience. 2020;14:27.
doi:10.3389/fncel.2020.00027 .

Kisler, Kassandra, Nikolakopoulou, Angeliki M., Sweeney, Melanie D., Lazić, Divna, Zhao, Zhen, Zloković, Berislav V., "Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling" in Frontiers in Cellular Neuroscience, 14 (2020):27,
https://doi.org/10.3389/fncel.2020.00027 . .

TY  - JOUR
AU  - Nikolakopoulou, Angeliki M.
AU  - Montagne, Axel
AU  - Kisler, Kassandra
AU  - Dai, Zhonghua
AU  - Wang, Yaoming
AU  - Huuskonen, Mikko T.
AU  - Sagare, Abhay P.
AU  - Lazić, Divna
AU  - Sweeney, Melanie D.
AU  - Kong, Pan
AU  - Wang, Min
AU  - Owens, Nelly Chuqui
AU  - Lawson, Erica J.
AU  - Xie, Xiaochun
AU  - Zhao, Zhen
AU  - Zloković, Berislav V.
PY  - 2019
UR  - http://www.nature.com/articles/s41593-019-0434-z
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3388
AB  - Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here we generate an inducible pericyte-specific Cre line and cross pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor. After pericyte ablation with diphtheria toxin, mice showed acute blood-brain barrier breakdown, severe loss of blood flow, and a rapid neuron loss that was associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing of pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade that links pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings may have implications for the pathogenesis and treatment of neurological disorders that are associated with pericyte loss and/or neurovascular dysfunction.
T2  - Nature Neuroscience
T1  - Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss.
IS  - 7
VL  - 22
DO  - 10.1038/s41593-019-0434-z
SP  - 1089
EP  - 1098
ER  - 

@article{
author = "Nikolakopoulou, Angeliki M. and Montagne, Axel and Kisler, Kassandra and Dai, Zhonghua and Wang, Yaoming and Huuskonen, Mikko T. and Sagare, Abhay P. and Lazić, Divna and Sweeney, Melanie D. and Kong, Pan and Wang, Min and Owens, Nelly Chuqui and Lawson, Erica J. and Xie, Xiaochun and Zhao, Zhen and Zloković, Berislav V.",
year = "2019",
abstract = "Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here we generate an inducible pericyte-specific Cre line and cross pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor. After pericyte ablation with diphtheria toxin, mice showed acute blood-brain barrier breakdown, severe loss of blood flow, and a rapid neuron loss that was associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing of pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade that links pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings may have implications for the pathogenesis and treatment of neurological disorders that are associated with pericyte loss and/or neurovascular dysfunction.",
journal = "Nature Neuroscience",
title = "Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss.",
number = "7",
volume = "22",
doi = "10.1038/s41593-019-0434-z",
pages = "1089-1098"
}

Nikolakopoulou, A. M., Montagne, A., Kisler, K., Dai, Z., Wang, Y., Huuskonen, M. T., Sagare, A. P., Lazić, D., Sweeney, M. D., Kong, P., Wang, M., Owens, N. C., Lawson, E. J., Xie, X., Zhao, Z.,& Zloković, B. V.. (2019). Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss.. in Nature Neuroscience, 22(7), 1089-1098.
https://doi.org/10.1038/s41593-019-0434-z

Nikolakopoulou AM, Montagne A, Kisler K, Dai Z, Wang Y, Huuskonen MT, Sagare AP, Lazić D, Sweeney MD, Kong P, Wang M, Owens NC, Lawson EJ, Xie X, Zhao Z, Zloković BV. Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss.. in Nature Neuroscience. 2019;22(7):1089-1098.
doi:10.1038/s41593-019-0434-z .

Nikolakopoulou, Angeliki M., Montagne, Axel, Kisler, Kassandra, Dai, Zhonghua, Wang, Yaoming, Huuskonen, Mikko T., Sagare, Abhay P., Lazić, Divna, Sweeney, Melanie D., Kong, Pan, Wang, Min, Owens, Nelly Chuqui, Lawson, Erica J., Xie, Xiaochun, Zhao, Zhen, Zloković, Berislav V., "Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss." in Nature Neuroscience, 22, no. 7 (2019):1089-1098,
https://doi.org/10.1038/s41593-019-0434-z . .

TY  - JOUR
AU  - Kisler, Kassandra
AU  - Lazić, Divna
AU  - Sweeney, Melanie D
AU  - Plunkett, Shane
AU  - El Khatib, Mirna
AU  - Vinogradov, Sergei A
AU  - Boas, David A
AU  - Sakadži, Sava
AU  - Zloković, Berislav V
PY  - 2018
UR  - http://www.nature.com/doifinder/10.1038/nprot.2018.034
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3081
AB  - Cerebrovascular dysfunction has an important role in the pathogenesis of multiple brain disorders. Measurement of hemodynamic responses in vivo can be challenging, particularly as techniques are often not described in sufficient detail and vary between laboratories. We present a set of standardized in vivo protocols that describe high-resolution two-photon microscopy and intrinsic optical signal (IOS) imaging to evaluate capillary and arteriolar responses to a stimulus, regional hemodynamic responses, and oxygen delivery to the brain. The protocol also describes how to measure intrinsic NADH fluorescence to understand how blood O2 supply meets the metabolic demands of activated brain tissue, and to perform resting-state absolute oxygen partial pressure (pO2) measurements of brain tissue. These methods can detect cerebrovascular changes at far higher resolution than MRI techniques, although the optical nature of these techniques limits their achievable imaging depths. Each individual procedure requires 1-2 h to complete, with two to three procedures typically performed per animal at a time. These protocols are broadly applicable in studies of cerebrovascular function in healthy and diseased brain in any of the existing mouse models of neurological and vascular disorders. All these procedures can be accomplished by a competent graduate student or experienced technician, except the two-photon measurement of absolute pO2 level, which is better suited to a more experienced, postdoctoral-level researcher.
T2  - Nature Protocols
T1  - In vivo imaging and analysis of cerebrovascular hemodynamic responses and tissue oxygenation in the mouse brain.
IS  - 6
VL  - 13
DO  - 10.1038/nprot.2018.034
SP  - 1377
EP  - 1402
ER  - 

@article{
author = "Kisler, Kassandra and Lazić, Divna and Sweeney, Melanie D and Plunkett, Shane and El Khatib, Mirna and Vinogradov, Sergei A and Boas, David A and Sakadži, Sava and Zloković, Berislav V",
year = "2018",
abstract = "Cerebrovascular dysfunction has an important role in the pathogenesis of multiple brain disorders. Measurement of hemodynamic responses in vivo can be challenging, particularly as techniques are often not described in sufficient detail and vary between laboratories. We present a set of standardized in vivo protocols that describe high-resolution two-photon microscopy and intrinsic optical signal (IOS) imaging to evaluate capillary and arteriolar responses to a stimulus, regional hemodynamic responses, and oxygen delivery to the brain. The protocol also describes how to measure intrinsic NADH fluorescence to understand how blood O2 supply meets the metabolic demands of activated brain tissue, and to perform resting-state absolute oxygen partial pressure (pO2) measurements of brain tissue. These methods can detect cerebrovascular changes at far higher resolution than MRI techniques, although the optical nature of these techniques limits their achievable imaging depths. Each individual procedure requires 1-2 h to complete, with two to three procedures typically performed per animal at a time. These protocols are broadly applicable in studies of cerebrovascular function in healthy and diseased brain in any of the existing mouse models of neurological and vascular disorders. All these procedures can be accomplished by a competent graduate student or experienced technician, except the two-photon measurement of absolute pO2 level, which is better suited to a more experienced, postdoctoral-level researcher.",
journal = "Nature Protocols",
title = "In vivo imaging and analysis of cerebrovascular hemodynamic responses and tissue oxygenation in the mouse brain.",
number = "6",
volume = "13",
doi = "10.1038/nprot.2018.034",
pages = "1377-1402"
}

Kisler, K., Lazić, D., Sweeney, M. D., Plunkett, S., El Khatib, M., Vinogradov, S. A., Boas, D. A., Sakadži, S.,& Zloković, B. V.. (2018). In vivo imaging and analysis of cerebrovascular hemodynamic responses and tissue oxygenation in the mouse brain.. in Nature Protocols, 13(6), 1377-1402.
https://doi.org/10.1038/nprot.2018.034

Kisler K, Lazić D, Sweeney MD, Plunkett S, El Khatib M, Vinogradov SA, Boas DA, Sakadži S, Zloković BV. In vivo imaging and analysis of cerebrovascular hemodynamic responses and tissue oxygenation in the mouse brain.. in Nature Protocols. 2018;13(6):1377-1402.
doi:10.1038/nprot.2018.034 .

Kisler, Kassandra, Lazić, Divna, Sweeney, Melanie D, Plunkett, Shane, El Khatib, Mirna, Vinogradov, Sergei A, Boas, David A, Sakadži, Sava, Zloković, Berislav V, "In vivo imaging and analysis of cerebrovascular hemodynamic responses and tissue oxygenation in the mouse brain." in Nature Protocols, 13, no. 6 (2018):1377-1402,
https://doi.org/10.1038/nprot.2018.034 . .