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Cerebral venous congestion exacerbates cerebral microhemorrhages in mice

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Abstract

Cerebral microhemorrhages (CMHs; microbleeds), which are small focal intracerebral hemorrhages, importantly contribute to the pathogenesis of cognitive decline and dementia in older adults. Although recently it has been increasingly recognized that the venous side of the cerebral circulation likely plays a fundamental role in the pathogenesis of a wide spectrum of cerebrovascular and brain disorders, its role in the pathogenesis of CMHs has never been studied. The present study was designed to experimentally test the hypothesis that venous congestion can exacerbate the genesis of CMHs. Increased cerebral venous pressure was induced by internal and external jugular vein ligation (JVL) in C57BL/6 mice in which systemic hypertension was induced by treatment with angiotensin II plus L-NAME. Histological analysis (diaminobenzidine staining) showed that mice with JVL developed multiple CMHs. CMHs in mice with JVL were often localized adjacent to veins and venules and their morphology was consistent with venous origin of the bleeds. In brains of mice with JVL, a higher total count of CMHs was observed compared to control mice. CMHs were distributed widely in the brain of mice with JVL, including the cortical gray matter, brain stem, the basal ganglia, subcortical white matter, cerebellum, and the hippocampi. In mice with JVL, there were more CMHs predominantly in cerebral cortex, brain stem, and cerebellum than in control mice. CMH burden, defined as total CMH volume, also significantly increased in mice with JVL. Thus, cerebral venous congestion can exacerbate CMHs. These observations have relevance to the pathogenesis of cognitive impairment associated with right heart failure as well as elevated cerebral venous pressure due to jugular venous reflux in older adults.

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Funding

This work was supported by grants from the American Heart Association (AHA834339), the Oklahoma Center for the Advancement of Science and Technology, the National Institute on Aging (R01-AG055395, R01-AG047879; R01-AG038747; K01-AG073614), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS100782, R01-NS056218), 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), the Presbyterian Health Foundation, 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; the National Research, Development and Innovation Office (NKFI-FK123798; Nemzeti Szivlabor), the Hungarian Academy of Sciences (Bolyai Research Scholarship BO/00634/15), and the ÚNKP-18–4-PTE-6 New National Excellence Program of the Ministry of Human Capacities (to PT). The Thematic Excellence Programme of the Ministry for Innovation and Technology was also supported by the National Research, Development and Innovation Fund of Hungary (Nos. TKP2020-IKA-04 and TKP2020-NKA-04) within the frameworks of the preclinical thematic programme of the University of Debrecen. The authors acknowledge the support from the NIA-funded Geroscience Training Program in Oklahoma (T32AG052363). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Author notes

  1. Adam Nyul-Toth, Gabor A. Fulop, Stefano Tarantini, Tamas Kiss, Anna Csiszar, Chetan Ahire and Janet A Faakye contributed equally to this work.

Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10thStreet, BRC 1313, Oklahoma City, OK, 73104, USA

    Adam Nyul-Toth, Gabor A. Fulop, Stefano Tarantini, Tamas Kiss, Chetan Ahire, Janet A. Faakye, Anna Ungvari, Peter Toth, Anna Csiszar & Zoltan Ungvari

  2. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary

    Adam Nyul-Toth, Stefano Tarantini, Tamas Kiss & Zoltan Ungvari

  3. International Training Program in Geroscience, Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network (ELKH), Szeged, Hungary

    Adam Nyul-Toth

  4. Heart and Vascular Center, Semmelweis University, Budapest, Hungary

    Gabor A. Fulop

  5. International Training Program in Geroscience, Division of Clinical Physiology, Department of Cardiology / Doctoral School of Kálmán Laki, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Gabor A. Fulop & Attila Toth

  6. First Department of Pediatrics, International Training Program in Geroscience, Semmelweis University, Budapest, Hungary

    Tamas Kiss

  7. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Institute of Translational Medicine, Semmelweis University, Budapest, Hungary

    Tamas Kiss & Anna Csiszar

  8. International Training Program in Geroscience, Department of Neurosurgery and Szentagothai Research Center, University of Pecs, Medical School, Pecs, Hungary

    Peter Toth

  9. MTA-PTE Clinical Neuroscience MR Research Group, Pecs, Hungary

    Peter Toth

  10. HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary

    Attila Toth

  11. Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Attila Toth

  12. Theoretical Medicine Doctoral School, International Training Program in Geroscience, University of Szeged, Szeged, Hungary

    Anna Csiszar & Zoltan Ungvari

  13. The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Anna Csiszar & Zoltan Ungvari

  14. Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Zoltan Ungvari

Authors
  1. Adam Nyul-Toth
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  2. Gabor A. Fulop
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  3. Stefano Tarantini
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  4. Tamas Kiss
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  5. Chetan Ahire
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  6. Janet A. Faakye
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  7. Anna Ungvari
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  8. Peter Toth
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  9. Attila Toth
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  10. Anna Csiszar
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  11. Zoltan Ungvari
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Corresponding author

Correspondence to Adam Nyul-Toth.

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Competing interests

Dr. Anna Csiszar serves as Associate Editor for The Journal of Gerontology, Series A: Biological Sciences and Medical Sciences and GeroScience. Dr. Stefano Tarantini serves as Guest Editor for Frontiers in Aging Neuroscience. Dr. Zoltan Ungvari serves as Editor-in-Chief for GeroScience and as Consulting Editor for The American Journal of Physiology-Heart and Circulatory Physiology.

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Nyul-Toth, A., Fulop, G.A., Tarantini, S. et al. Cerebral venous congestion exacerbates cerebral microhemorrhages in mice. GeroScience 44, 805–816 (2022). https://doi.org/10.1007/s11357-021-00504-0

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  • DOI: https://doi.org/10.1007/s11357-021-00504-0

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