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Fusogenic liposomes effectively deliver resveratrol to the cerebral microcirculation and improve endothelium-dependent neurovascular coupling responses in aged mice

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Abstract

Adjustment of cerebral blood flow (CBF) to the increased oxygen and nutrient demands of active brain regions via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In advanced age, cerebromicrovascular oxidative stress and endothelial dysfunction impair neurovascular coupling, contributing to age-related cognitive decline. Recently we developed a resveratrol (3,4′,5-trihydroxystilbene)-containing fusogenic liposome (FL-RSV)-based molecular delivery system that can effectively target cultured cerebromicrovascular endothelial cells, attenuating age-related oxidative stress. To assess the cerebromicrovascular protective effects of FL-RSV in vivo, aged (24-month-old) C57BL/6 mice were treated with FL-RSV for four days. To demonstrate effective cellular uptake of FL-RSV, accumulation of the lipophilic tracer dyes in cells of the neurovascular unit was confirmed using two-photon imaging (through a chronic cranial window). NVC was assessed by measuring CBF responses (laser speckle contrast imaging) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. Treatment with FL-RSV significantly improved NVC responses by increasing NO-mediated vasodilation. These findings are paralleled by the protective effects of FL-RSV on endothelium-dependent relaxation in the aorta. Thus, treatment with FL-RSV rescues endothelial function and NVC responses in aged mice. We propose that resveratrol containing fusogenic liposomes could also be used for combined delivery of various anti-geronic factors, including proteins, small molecules, DNA vectors and mRNAs targeting key pathways involved in microvascular aging and neurovascular dysfunction for the prevention/treatment of age-related cerebromicrovascular pathologies and development of vascular cognitive impairment (VCI) in aging.

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Acknowledgements

This collaborative research project was conducted within the framework of the International Geroscience Training Program of the Oklahoma Center for Geroscience. 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 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), the Presbyterian Health Foundation (to ZU, AC, AY), the NIA-supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), and the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337). The funding sources had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

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  1. Tabea Wiedenhoeft, Stefano Tarantini, Ádám Nyúl-Tóth and Andriy Yabluchanskiy contributed equally to this work.

Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Oklahoma Center for Geroscience, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Tabea Wiedenhoeft, Stefano Tarantini, Ádám Nyúl-Tóth, Andriy Yabluchanskiy, Tamas Csipo, Priya Balasubramanian, Agnes Lipecz, Tamas Kiss, Anna Csiszar & Zoltan Ungvari

  2. Institute of Complex Systems, ICS-7: Biomechanics, Forschungszentrum Jülich GmbH, 52425, Jülich, Germany

    Tabea Wiedenhoeft & Agnes Csiszar

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

    Stefano Tarantini, Tamas Csipo, Agnes Lipecz & Zoltan Ungvari

  4. Institute of Biophysics, Biological Research Centre, Szeged, Hungary

    Ádám Nyúl-Tóth

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

    Tamas Csipo

  6. International Training Program in Geroscience,Theoretical Medicine Doctoral School/Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary

    Tamas Kiss & Anna Csiszar

  7. Doctoral School of Basic and Translational Medicine/Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary

    Anna Csiszar & Zoltan Ungvari

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

    Zoltan Ungvari

  9. 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

    Zoltan Ungvari

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  1. Tabea Wiedenhoeft
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  2. Stefano Tarantini
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  4. Andriy Yabluchanskiy
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  8. Tamas Kiss
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  9. Anna Csiszar
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  11. Zoltan Ungvari
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Correspondence to Zoltan Ungvari.

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Wiedenhoeft, T., Tarantini, S., Nyúl-Tóth, Á. et al. Fusogenic liposomes effectively deliver resveratrol to the cerebral microcirculation and improve endothelium-dependent neurovascular coupling responses in aged mice. GeroScience 41, 711–725 (2019). https://doi.org/10.1007/s11357-019-00102-1

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