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Endothelial deficiency of insulin-like growth factor-1 receptor (IGF1R) impairs neurovascular coupling responses in mice, mimicking aspects of the brain aging phenotype

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Abstract

Age-related impairment of neurovascular coupling (NVC; or “functional hyperemia”) compromises moment-to-moment adjustment of regional cerebral blood flow to increased neuronal activity and thereby contributes to the pathogenesis of vascular cognitive impairment (VCI). Previous studies established a causal link among age-related decline in circulating levels of insulin-like growth factor-1 (IGF-1), neurovascular dysfunction and cognitive impairment. Endothelium-mediated microvascular dilation plays a central role in NVC responses. To determine the functional consequences of impaired IGF-1 input to cerebromicrovascular endothelial cells, endothelium-mediated NVC responses were studied in a novel mouse model of accelerated neurovascular aging: mice with endothelium-specific knockout of IGF1R (VE-Cadherin-CreERT2/Igf1rf/f). Increases in cerebral blood flow in the somatosensory whisker barrel cortex (assessed using laser speckle contrast imaging through a cranial window) in response to contralateral whisker stimulation were significantly attenuated in VE-Cadherin-CreERT2/Igf1rf/f mice as compared to control mice. In VE-Cadherin-CreERT2/Igf1rf/f mice, the effects of the NO synthase inhibitor L-NAME were significantly decreased, suggesting that endothelium-specific disruption of IGF1R signaling impairs the endothelial NO-dependent component of NVC responses. Collectively, these findings provide additional evidence that IGF-1 is critical for cerebromicrovascular endothelial health and maintenance of normal NVC responses.

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Acknowledgements

This work was supported by grants from the American Heart Association, the American Federation for Aging Research (Irene/Diamond Postdoctoral Transition Award to PB), the Oklahoma Center for the Advancement of Science and Technology, the National Institute on Aging ((R01-AG055395, R01-AG047879; R01-AG038747; R01-AG072295), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS100782), the National Cancer Institute (NCI;1R01CA255840), the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (U54GM104938, to AY), the Presbyterian Health Foundation and the NKFIH (Nemzeti Szivlabor). The authors acknowledge the support from the NIA-funded Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), 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. Stefano Tarantini, Ádám Nyúl-Tóth, and Andriy Yabluchanskiy 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 & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 731042, USA

    Stefano Tarantini, Ádám Nyúl-Tóth, Andriy Yabluchanskiy, Tamas Csipo, Peter Mukli, Priya Balasubramanian, Anna Ungvari, William E. Sonntag, Zoltan Ungvari & Anna Csiszar

  2. International Training Program in Geroscience, Oklahoma Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 731042, USA

    Stefano Tarantini, Ádám Nyúl-Tóth, Andriy Yabluchanskiy, Tamas Csipo, Peter Mukli, Zoltan Ungvari & Anna Csiszar

  3. Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK, 73104, USA

    Stefano Tarantini, Zoltan Ungvari & Anna Csiszar

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

    Stefano Tarantini, Andriy Yabluchanskiy & Zoltan Ungvari

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

    Stefano Tarantini, Ádám Nyúl-Tóth, Tamas Csipo, Peter Toth & Zoltan Ungvari

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

    Ádám Nyúl-Tóth

  7. International Training Program in Geroscience, Department of Physiology, Semmelweis University, Budapest, Hungary

    Peter Mukli

  8. Department of Neurosurgery, University of Pécs Clinical Center, 72359, Pecs, Baranya, Hungary

    Peter Toth

  9. Vascular Cognitive Impairment and Neurodegeneration Program, Department of Translational Medicine, Semmelweis University, Budapest, Hungary

    Zoltan Benyo & Anna Csiszar

  10. Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences, Center 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA

    Anna Csiszar

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  1. Stefano Tarantini
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  2. Ádám Nyúl-Tóth
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  7. Anna Ungvari
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  10. William E. Sonntag
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Correspondence to Anna Csiszar.

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Disclosures

Dr. Anna Csiszar serves as Associate Editor for The Journal of Gerontology, Series A: Biological Sciences and Medical Sciences and GeroScience. Dr. Andriy Yabluchanskiy serves as Guest Editor for The American Journal of Physiology-Heart and Circulatory Physiology. Dr. William E. Sonntag serves as Associate Editor for The Journal of Gerontology, Series A: Biological Sciences and GeroScience. Dr. Zoltan Ungvari serves as Associate Editor for The Journal of Gerontology, Series A: Biological Sciences, Editor-in-Chief for GeroScience and as Consulting Editor for The American Journal of Physiology-Heart and Circulatory Physiology.

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Tarantini, S., Nyúl-Tóth, Á., Yabluchanskiy, A. et al. Endothelial deficiency of insulin-like growth factor-1 receptor (IGF1R) impairs neurovascular coupling responses in mice, mimicking aspects of the brain aging phenotype. GeroScience 43, 2387–2394 (2021). https://doi.org/10.1007/s11357-021-00405-2

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  • DOI: https://doi.org/10.1007/s11357-021-00405-2

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