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Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for the prevention of vascular cognitive impairment

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Abstract

Age-related impairment of angiogenesis likely has a critical role in cerebromicrovascular rarefaction and development of vascular cognitive impairment and dementia (VCID) in the elderly. Recently, we demonstrated that aging is associated with NAD+ depletion in the vasculature and that administration of NAD+ precursors exerts potent anti-aging vascular effects, rescuing endothelium-mediated vasodilation in the cerebral circulation and improving cerebral blood supply. The present study was designed to elucidate how treatment with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, impacts age-related impairment of endothelial angiogenic processes. Using cerebromicrovascular endothelial cells (CMVECs) isolated from young and aged F344xBN rats, we demonstrated that compared with young cells, aged CMVECs exhibit impaired proliferation, cellular migration (measured by a wound-healing assay using electric cell-substrate impedance sensing [ECIS] technology), impaired ability to form capillary-like structures, and increased oxidative stress. NMN treatment in aged CMVECs significantly improved angiogenic processes and attenuated H2O2 production. We also found that pre-treatment with EX-527, a pharmacological inhibitor of SIRT1, prevented NMN-mediated restoration of angiogenic processes in aged CMVECs. Collectively, we find that normal cellular NAD+ levels are essential for normal endothelial angiogenic processes, suggesting that age-related cellular NAD+ depletion and consequential SIRT1 dysregulation may be a potentially reversible mechanism underlying impaired angiogenesis and cerebromicrovascular rarefaction in aging. We recommend that pro-angiogenic effects of NAD+ boosters should be considered in both preclinical and clinical studies.

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Funding

This work was supported by grants from the American Heart Association (ST, MNVA), the Oklahoma Center for the Advancement of Science and Technology (to AC, AY, ZU), the National Institute on Aging (R01-AG047879; R01-AG038747; R01-AG055395), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218 to AC, R01-NS100782 to ZU), the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (GM104938, to AY), and the Presbyterian Health Foundation (to ZU, AC, AY).

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  1. Tamas Kiss, Priya Balasubramanian, Marta Noa Valcarcel-Ares and Stefano Tarantini contributed equally to this work.

Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA

    Tamas Kiss, Priya Balasubramanian, Marta Noa Valcarcel-Ares, Stefano Tarantini, Andriy Yabluchanskiy, Tamas Csipo, Agnes Lipecz, Anna Csiszar & Zoltan Ungvari

  2. Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary

    Tamas Kiss, Tamas Csipo, Agnes Lipecz, Ferenc Bari, Eszter Farkas, Anna Csiszar & Zoltan Ungvari

  3. Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary

    Tamas Kiss, Ferenc Bari, Eszter Farkas, Anna Csiszar & Zoltan Ungvari

  4. Department of Anatomy, MTA-PTE PACAP Research Team, University of Pecs Medical School, Pecs, Hungary

    Dora Reglodi

  5. Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Xin A. Zhang

  6. Department of Public Health, Semmelweis University, Budapest, Hungary

    Zoltan Ungvari

  7. Department of Health Promotion Sciences, the Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Zoltan Ungvari

Authors
  1. Tamas Kiss
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  2. Priya Balasubramanian
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  3. Marta Noa Valcarcel-Ares
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  4. Stefano Tarantini
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  5. Andriy Yabluchanskiy
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  6. Tamas Csipo
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  7. Agnes Lipecz
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  9. Xin A. Zhang
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  10. Ferenc Bari
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  11. Eszter Farkas
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  12. Anna Csiszar
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  13. Zoltan Ungvari
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Corresponding author

Correspondence to Zoltan Ungvari.

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Kiss, T., Balasubramanian, P., Valcarcel-Ares, M.N. et al. Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for the prevention of vascular cognitive impairment. GeroScience 41, 619–630 (2019). https://doi.org/10.1007/s11357-019-00074-2

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