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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 UngvariEmail author
Original Article


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.


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



The authors acknowledge the support from the NIA-funded Geroscience Training Program in Oklahoma (T32AG052363).

Funding information

This work was supported by grants from the American Heart Association (ST), the Oklahoma Center for the Advancement of Science and Technology (to AC, AY, PB, ZU), the American Federation for Aging Research (to PB), the National Institute on Aging (R01-AG055395, R01-AG047879, R01-AG038747), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS100782, R01-NS056218), and the Department of Veterans Affairs (Merit Number 1I01CX000340); a Pilot Grant from the Stephenson Cancer Center funded by the National Cancer Institute Cancer Center Support Grant P30CA225520 awarded to the University of Oklahoma Stephenson Cancer Center, the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (U54GM104938, to AY), and the Presbyterian Health Foundation (to ZU, AC, AY); the European Union–funded grants EFOP-3.6.1-16-2016-00008, 20765-3/2018/FEKUTSTRAT, EFOP-3.6.2.-16-2017-00008, GINOP-2.3.2-15-2016-00048, and GINOP-2.3.3-15-2016-00032; a grant from the National Research, Development and Innovation Office (NKFI-FK123798); a grant from the Hungarian Academy of Sciences (Bolyai Research Scholarship BO/00634/15); and a grant from the ÚNKP-18-4-PTE-6 New National Excellence Program of the Ministry of Human Capacities (to PT).

Compliance with ethical standards

All procedures were approved by the Institutional Animal Use and Care Committees of the University of Oklahoma Health Sciences Center.

Conflict of interest

The authors declare that they have no conflict of interest.


The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


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Copyright information

© American Aging Association 2019

Authors and Affiliations

  • Gabor A. Fulop
    • 1
    • 2
    • 3
  • Chetan Ahire
    • 1
  • Tamas Csipo
    • 1
    • 2
    • 4
  • Stefano Tarantini
    • 1
    • 4
  • Tamas Kiss
    • 1
    • 5
  • Priya Balasubramanian
    • 1
  • Andriy Yabluchanskiy
    • 1
  • Eszter Farkas
    • 5
  • Attila Toth
    • 2
  • Ádám Nyúl-Tóth
    • 1
    • 6
  • Peter Toth
    • 1
    • 7
    • 8
  • Anna Csiszar
    • 1
    • 5
    • 9
  • Zoltan Ungvari
    • 1
    • 4
    • 5
    Email author
  1. 1.Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience, Department of Biochemistry and Molecular BiologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.International Training Program in Geroscience, Division of Clinical Physiology, Department of Cardiology/Kálmán Laki Doctoral School of Biomedical and Clinical Sciences, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  3. 3.Heart and Vascular CenterSemmelweis UniversityBudapestHungary
  4. 4.International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public HealthSemmelweis UniversityBudapestHungary
  5. 5.International Training Program in Geroscience, Theoretical Medicine Doctoral School, Department of Medical Physics and InformaticsUniversity of SzegedSzegedHungary
  6. 6.International Training Program in Geroscience, Institute of BiophysicsBiological Research CentreSzegedHungary
  7. 7.International Training Program in Geroscience, Department of Neurosurgery and Szentagothai Research CenterUniversity of Pecs, Medical SchoolPecsHungary
  8. 8.Institute for Translational MedicineUniversity of Pecs, Medical School PecsHungary
  9. 9.International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Institute of Clinical Experimental ResearchSemmelweis UniversityBudapestHungary

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