Cerebral venous congestion promotes blood-brain barrier disruption and neuroinflammation, impairing cognitive function in mice

Gabor A. Fulop, Chetan Ahire, Tamas Csipo, Stefano Tarantini, Tamas Kiss, Priya Balasubramanian, Andriy Yabluchanskiy, Eszter Farkas, Attila Toth, Ádám Nyúl-Tóth, Peter Toth, Anna Csiszar, Zoltan Ungvari

Research output: Contribution to journalArticle

Abstract

Cognitive impairment is one of the most common co-occurring chronic conditions among elderly heart failure patients (incidence: up to ~ 80%); however, the underlying mechanisms are not completely understood. It is hypothesized that in addition to decreased cardiac output, increases in central—and consequentially, cerebral—venous pressure (backward failure) also contribute significantly to the genesis of cognitive impairment. To test this hypothesis and elucidate the specific pathogenic role of venous congestion in the brain, we have established a novel model of increased cerebral venous pressure: mice with jugular vein ligation (JVL). To test the hypothesis that increased venous pressure in the brain contributes to the development of cognitive deficits by causing blood-brain barrier disruption, dysregulation of blood flow, and/or promoting neuroinflammation, in C57BL/6 mice, the internal and external jugular veins were ligated. Cognitive function (radial arm water maze), gait function (CatWalk), and motor coordination (rotarod) were tested post-JVL. Neurovascular coupling responses were assessed by measuring changes in cerebral blood flow in the whisker barrel cortex in response to contralateral whisker stimulation by laser speckle contrast imaging through a closed cranial window. Blood-brain barrier integrity (IgG extravasation) and microglia activation (Iba1 staining) were assessed in brain slices by immunohistochemistry. Neuroinflammation-related gene expression profile was assessed by a targeted qPCR array. After jugular vein ligation, mice exhibited impaired spatial learning and memory, altered motor coordination, and impaired gait function, mimicking important aspects of altered brain function observed in human heart failure patients. JVL did not alter neurovascular coupling responses. In the brains of mice with JVL, significant extravasation of IgG was detected, indicating blood-brain barrier disruption, which was associated with histological markers of neuroinflammation (increased presence of activated microglia) and a pro-inflammatory shift in gene expression profile. Thus, cerebral venous congestion per se can cause blood-brain barrier disruption and neuroinflammation, which likely contribute to the genesis of cognitive impairment. These findings have relevance to the pathogenesis of cognitive decline associated with heart failure as well as increased cerebal venous pressure due to increased jugular venous reflux in elderly human patients.

Original languageEnglish
JournalGeroScience
DOIs
Publication statusAccepted/In press - Jan 1 2019

Fingerprint

Jugular Veins
Hyperemia
Blood-Brain Barrier
Cognition
Ligation
Venous Pressure
Brain
Vibrissae
Heart Failure
Microglia
Gait
Transcriptome
Cerebrovascular Circulation
Immunoglobulin G
Inbred C57BL Mouse
Cardiac Output
Lasers
Neck
Immunohistochemistry
Staining and Labeling

Keywords

  • Cerebral circulation
  • Vascular cognitive impairment
  • Vascular contributions to cognitive impairment and dementia (VCID)
  • VCI
  • Vein

ASJC Scopus subject areas

  • Ageing
  • Geriatrics and Gerontology

Cite this

Fulop, G. A., Ahire, C., Csipo, T., Tarantini, S., Kiss, T., Balasubramanian, P., ... Ungvari, Z. (Accepted/In press). Cerebral venous congestion promotes blood-brain barrier disruption and neuroinflammation, impairing cognitive function in mice. GeroScience. https://doi.org/10.1007/s11357-019-00110-1

Cerebral venous congestion promotes blood-brain barrier disruption and neuroinflammation, impairing cognitive function in mice. / Fulop, Gabor A.; Ahire, Chetan; Csipo, Tamas; Tarantini, Stefano; Kiss, Tamas; Balasubramanian, Priya; Yabluchanskiy, Andriy; Farkas, Eszter; Toth, Attila; Nyúl-Tóth, Ádám; Toth, Peter; Csiszar, Anna; Ungvari, Zoltan.

In: GeroScience, 01.01.2019.

Research output: Contribution to journalArticle

Fulop, GA, Ahire, C, Csipo, T, Tarantini, S, Kiss, T, Balasubramanian, P, Yabluchanskiy, A, Farkas, E, Toth, A, Nyúl-Tóth, Á, Toth, P, Csiszar, A & Ungvari, Z 2019, 'Cerebral venous congestion promotes blood-brain barrier disruption and neuroinflammation, impairing cognitive function in mice', GeroScience. https://doi.org/10.1007/s11357-019-00110-1
Fulop, Gabor A. ; Ahire, Chetan ; Csipo, Tamas ; Tarantini, Stefano ; Kiss, Tamas ; Balasubramanian, Priya ; Yabluchanskiy, Andriy ; Farkas, Eszter ; Toth, Attila ; Nyúl-Tóth, Ádám ; Toth, Peter ; Csiszar, Anna ; Ungvari, Zoltan. / Cerebral venous congestion promotes blood-brain barrier disruption and neuroinflammation, impairing cognitive function in mice. In: GeroScience. 2019.
@article{30e68a41ecd6492fba2e2ed1ba46e305,
title = "Cerebral venous congestion promotes blood-brain barrier disruption and neuroinflammation, impairing cognitive function in mice",
abstract = "Cognitive impairment is one of the most common co-occurring chronic conditions among elderly heart failure patients (incidence: up to ~ 80{\%}); however, the underlying mechanisms are not completely understood. It is hypothesized that in addition to decreased cardiac output, increases in central—and consequentially, cerebral—venous pressure (backward failure) also contribute significantly to the genesis of cognitive impairment. To test this hypothesis and elucidate the specific pathogenic role of venous congestion in the brain, we have established a novel model of increased cerebral venous pressure: mice with jugular vein ligation (JVL). To test the hypothesis that increased venous pressure in the brain contributes to the development of cognitive deficits by causing blood-brain barrier disruption, dysregulation of blood flow, and/or promoting neuroinflammation, in C57BL/6 mice, the internal and external jugular veins were ligated. Cognitive function (radial arm water maze), gait function (CatWalk), and motor coordination (rotarod) were tested post-JVL. Neurovascular coupling responses were assessed by measuring changes in cerebral blood flow in the whisker barrel cortex in response to contralateral whisker stimulation by laser speckle contrast imaging through a closed cranial window. Blood-brain barrier integrity (IgG extravasation) and microglia activation (Iba1 staining) were assessed in brain slices by immunohistochemistry. Neuroinflammation-related gene expression profile was assessed by a targeted qPCR array. After jugular vein ligation, mice exhibited impaired spatial learning and memory, altered motor coordination, and impaired gait function, mimicking important aspects of altered brain function observed in human heart failure patients. JVL did not alter neurovascular coupling responses. In the brains of mice with JVL, significant extravasation of IgG was detected, indicating blood-brain barrier disruption, which was associated with histological markers of neuroinflammation (increased presence of activated microglia) and a pro-inflammatory shift in gene expression profile. Thus, cerebral venous congestion per se can cause blood-brain barrier disruption and neuroinflammation, which likely contribute to the genesis of cognitive impairment. These findings have relevance to the pathogenesis of cognitive decline associated with heart failure as well as increased cerebal venous pressure due to increased jugular venous reflux in elderly human patients.",
keywords = "Cerebral circulation, Vascular cognitive impairment, Vascular contributions to cognitive impairment and dementia (VCID), VCI, Vein",
author = "Fulop, {Gabor A.} and Chetan Ahire and Tamas Csipo and Stefano Tarantini and Tamas Kiss and Priya Balasubramanian and Andriy Yabluchanskiy and Eszter Farkas and Attila Toth and {\'A}d{\'a}m Ny{\'u}l-T{\'o}th and Peter Toth and Anna Csiszar and Zoltan Ungvari",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s11357-019-00110-1",
language = "English",
journal = "GeroScience",
issn = "2509-2715",
publisher = "Springer International Publishing AG",

}

TY - JOUR

T1 - Cerebral venous congestion promotes blood-brain barrier disruption and neuroinflammation, impairing cognitive function in mice

AU - Fulop, Gabor A.

AU - Ahire, Chetan

AU - Csipo, Tamas

AU - Tarantini, Stefano

AU - Kiss, Tamas

AU - Balasubramanian, Priya

AU - Yabluchanskiy, Andriy

AU - Farkas, Eszter

AU - Toth, Attila

AU - Nyúl-Tóth, Ádám

AU - Toth, Peter

AU - Csiszar, Anna

AU - Ungvari, Zoltan

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Cognitive impairment is one of the most common co-occurring chronic conditions among elderly heart failure patients (incidence: up to ~ 80%); however, the underlying mechanisms are not completely understood. It is hypothesized that in addition to decreased cardiac output, increases in central—and consequentially, cerebral—venous pressure (backward failure) also contribute significantly to the genesis of cognitive impairment. To test this hypothesis and elucidate the specific pathogenic role of venous congestion in the brain, we have established a novel model of increased cerebral venous pressure: mice with jugular vein ligation (JVL). To test the hypothesis that increased venous pressure in the brain contributes to the development of cognitive deficits by causing blood-brain barrier disruption, dysregulation of blood flow, and/or promoting neuroinflammation, in C57BL/6 mice, the internal and external jugular veins were ligated. Cognitive function (radial arm water maze), gait function (CatWalk), and motor coordination (rotarod) were tested post-JVL. Neurovascular coupling responses were assessed by measuring changes in cerebral blood flow in the whisker barrel cortex in response to contralateral whisker stimulation by laser speckle contrast imaging through a closed cranial window. Blood-brain barrier integrity (IgG extravasation) and microglia activation (Iba1 staining) were assessed in brain slices by immunohistochemistry. Neuroinflammation-related gene expression profile was assessed by a targeted qPCR array. After jugular vein ligation, mice exhibited impaired spatial learning and memory, altered motor coordination, and impaired gait function, mimicking important aspects of altered brain function observed in human heart failure patients. JVL did not alter neurovascular coupling responses. In the brains of mice with JVL, significant extravasation of IgG was detected, indicating blood-brain barrier disruption, which was associated with histological markers of neuroinflammation (increased presence of activated microglia) and a pro-inflammatory shift in gene expression profile. Thus, cerebral venous congestion per se can cause blood-brain barrier disruption and neuroinflammation, which likely contribute to the genesis of cognitive impairment. These findings have relevance to the pathogenesis of cognitive decline associated with heart failure as well as increased cerebal venous pressure due to increased jugular venous reflux in elderly human patients.

AB - Cognitive impairment is one of the most common co-occurring chronic conditions among elderly heart failure patients (incidence: up to ~ 80%); however, the underlying mechanisms are not completely understood. It is hypothesized that in addition to decreased cardiac output, increases in central—and consequentially, cerebral—venous pressure (backward failure) also contribute significantly to the genesis of cognitive impairment. To test this hypothesis and elucidate the specific pathogenic role of venous congestion in the brain, we have established a novel model of increased cerebral venous pressure: mice with jugular vein ligation (JVL). To test the hypothesis that increased venous pressure in the brain contributes to the development of cognitive deficits by causing blood-brain barrier disruption, dysregulation of blood flow, and/or promoting neuroinflammation, in C57BL/6 mice, the internal and external jugular veins were ligated. Cognitive function (radial arm water maze), gait function (CatWalk), and motor coordination (rotarod) were tested post-JVL. Neurovascular coupling responses were assessed by measuring changes in cerebral blood flow in the whisker barrel cortex in response to contralateral whisker stimulation by laser speckle contrast imaging through a closed cranial window. Blood-brain barrier integrity (IgG extravasation) and microglia activation (Iba1 staining) were assessed in brain slices by immunohistochemistry. Neuroinflammation-related gene expression profile was assessed by a targeted qPCR array. After jugular vein ligation, mice exhibited impaired spatial learning and memory, altered motor coordination, and impaired gait function, mimicking important aspects of altered brain function observed in human heart failure patients. JVL did not alter neurovascular coupling responses. In the brains of mice with JVL, significant extravasation of IgG was detected, indicating blood-brain barrier disruption, which was associated with histological markers of neuroinflammation (increased presence of activated microglia) and a pro-inflammatory shift in gene expression profile. Thus, cerebral venous congestion per se can cause blood-brain barrier disruption and neuroinflammation, which likely contribute to the genesis of cognitive impairment. These findings have relevance to the pathogenesis of cognitive decline associated with heart failure as well as increased cerebal venous pressure due to increased jugular venous reflux in elderly human patients.

KW - Cerebral circulation

KW - Vascular cognitive impairment

KW - Vascular contributions to cognitive impairment and dementia (VCID)

KW - VCI

KW - Vein

UR - http://www.scopus.com/inward/record.url?scp=85074926339&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074926339&partnerID=8YFLogxK

U2 - 10.1007/s11357-019-00110-1

DO - 10.1007/s11357-019-00110-1

M3 - Article

C2 - 31691147

AN - SCOPUS:85074926339

JO - GeroScience

JF - GeroScience

SN - 2509-2715

ER -