IGF1R signaling regulates astrocyte-mediated neurovascular coupling in mice: implications for brain aging.

Nyúl-Tóth Á

Tarantini S(#)(1)(2)(3)(4)(5), Balasubramanian P(#)(6), Yabluchanskiy A(#)(6)(7)(8), Ashpole NM(6)(9), Logan S(6)(10), Kiss T(6)(11), Ungvari A(6), Nyúl-Tóth Á(6)(12)(13), Schwartzman ML(14), Benyo Z(13), Sonntag WE(6), Csiszar A(6)(7)(15)(11)(13), Ungvari Z(6)(7)(8)(16)(11)(13).
Author information:
(1)Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Reynolds Oklahoma Center on Aging, Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA. [Email]
(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, 73104, USA. [Email]
(3)Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK, 73104, USA. [Email]
(4)Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. [Email]
(5)International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary. [Email]
(6)Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Reynolds Oklahoma Center on Aging, Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.
(7)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, 73104, USA.
(8)Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
(9)Pharmacology Division, Department of BioMolecular Sciences, University of Mississippi School of Pharmacy, Oxford, MS, USA.
(10)Department of Rehabilitation Sciences, College of Allied Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73117, USA.
(11)International Training Program in Geroscience, Theoretical Medicine Doctoral School/Departments of Medical Physics and Informatics & Cell Biology and Molecular Medicine, University of Szeged, Szeged, Hungary.
(12)International Training Program in Geroscience, Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network
(ELKH), Szeged, Hungary.
(13)Vascular Cognitive Impairment and Neurodegeneration Program/HCEMM, Department of Translational Medicine, Semmelweis University, Budapest, Hungary.
(14)Department of Pharmacology, New York Medical College School of Medicine, Valhalla, NY, USA.
(15)Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK, 73104, USA.
(16)International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary.
(#)Contributed equally

https://dx.doi.org/10.1007/s11357-021-00350-0

Aging is associated with a significant deficiency in circulating insulin-like growth factor-1 (IGF-1), which has an important role in the pathogenesis of age-related vascular cognitive impairment (VCI). Impairment of moment-to-moment adjustment of regional cerebral blood flow via neurovascular coupling (NVC) importantly contributes to VCI. Previous studies established a causal link between circulating IGF-1 deficiency and neurovascular dysfunction. Release of vasodilator mediators from activated astrocytes plays a key role in NVC. To determine the impact of impaired IGF-1 signaling on astrocytic function, astrocyte-mediated NVC responses were studied in a novel mouse model of astrocyte-specific knockout of IGF1R (GFAP-CreERT2/Igf1rf/f) and accelerated neurovascular aging. We found that mice with disrupted astrocytic IGF1R signaling exhibit impaired NVC responses, decreased stimulated release of the vasodilator gliotransmitter epoxy-eicosatrienoic acids (EETs), and upregulation of soluble epoxy hydrolase (sEH), which metabolizes and inactivates EETs. Collectively, our findings provide additional evidence that IGF-1 promotes astrocyte health and maintains normal NVC, protecting cognitive health.