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

doi:10.1007/s11357-021-00350-0

. 2021 Apr;43(2):901-911.

doi: 10.1007/s11357-021-00350-0. Epub 2021 Mar 6.

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

Stefano Tarantini^#^{1

2

3

4

5}, Priya Balasubramanian^#⁶, Andriy Yabluchanskiy^#^{6

7

8}, Nicole M Ashpole^{6

9}, Sreemathi Logan^{6

10}, Tamas Kiss^{6

11}, Anna Ungvari⁶, Ádám Nyúl-Tóth^{6

12

13}, Michal L Schwartzman¹⁴, Zoltan Benyo¹³, William E Sonntag⁶, Anna Csiszar^{6

7

15

11

13}, Zoltan Ungvari^{6

7

8

16

11

13}

Affiliations

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. stefano-tarantini@ouhsc.edu.
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. stefano-tarantini@ouhsc.edu.
³ Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK, 73104, USA. stefano-tarantini@ouhsc.edu.
⁴ Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. stefano-tarantini@ouhsc.edu.
⁵ International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary. stefano-tarantini@ouhsc.edu.
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.

PMID: 33674953
PMCID: PMC8110646
DOI: 10.1007/s11357-021-00350-0

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

Stefano Tarantini et al. Geroscience. 2021 Apr.

. 2021 Apr;43(2):901-911.

doi: 10.1007/s11357-021-00350-0. Epub 2021 Mar 6.

Authors

Affiliations

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. stefano-tarantini@ouhsc.edu.
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. stefano-tarantini@ouhsc.edu.
³ Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK, 73104, USA. stefano-tarantini@ouhsc.edu.
⁴ Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. stefano-tarantini@ouhsc.edu.
⁵ International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary. stefano-tarantini@ouhsc.edu.
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.

PMID: 33674953
PMCID: PMC8110646
DOI: 10.1007/s11357-021-00350-0

Abstract

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-Cre^ERT2/Igf1r^f/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.

Keywords: Arachidonic acid metabolites; Astrocyte; Cerebrovascular; Functional hyperemia; IGF-1; Insulin-like growth factor 1; Neurovascular aging; Neurovascular uncoupling; VCI; Vascular cognitive impairment.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1**
Astrocyte-specific disruption of IGF1R signaling impairs neurovascular coupling responses. a Representative pseudocolour laser speckle flowmetry maps of baseline CBF (upper row; shown for orientation purposes) and CBF changes in the whisker barrel field relative to baseline during contralateral whisker stimulation (bottom row, right oval, 30 s, 5 Hz) in control and *GFAP-Cre*^ERT2/Igf1r^f/f mice before and after administration of the P450 epoxygenase inhibitor MS-PPOH. Panel b shows the time-course of CBF changes after the start of contralateral whisker stimulation (horizontal bars). Summary data are shown in panel c. Data are mean ± S.E.M. (n=6–10 in each group), *P<0.05 vs. control; ^#P<0.05 vs. untreated. n.s. not significant

**Fig. 2**
Astrocyte-specific disruption of IGF1R signaling impairs glutamate-induced release of eicosanoid gliotransmitters. Shown is production of EETs in glutamate-activated brain slices from control and *GFAP-Cre*^ERT2/Igf1r^f/f mice, as measured by liquid chromatography/mass spectrometry (LC/MS). Data are mean ± S.E.M. (n=6–10 in each group), *P<0.05 vs. control (see the “Methods” section)

**Fig. 3**
Upregulation of sEH in mice with astrocyte-specific disruption of IGF1R signaling. a Representative Western blot showing upregulation of soluble epoxide hydrolase (sEH), a key enzyme in the metabolism of vasodilatory epoxyeicosatrienoic acids, and decreased expression of IGF1Rβ in cortical samples derived from tamoxifen-treated *GFAP-Cre*^ERT2/Igf1r^f/f mice, as compared to control mice. b–c Bar graphs are summary densitometric data showing expression of IGF1Rβ (a) and sEH (b), normalized to β-actin expression. Data are normalized to control mean values and are expressed as fold changes. Data are mean ± S.E.M. (n=6–10 in each group), *P<0.05 vs. control

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References

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[1] Gorelick PB, Counts SE, Nyenhuis D. Vascular cognitive impairment and dementia. Biochim Biophys Acta. 1862;2016:860–868. - PMC - PubMed

[2] Gorelick PB, Counts SE, Nyenhuis D. Vascular cognitive impairment and dementia. Biochim Biophys Acta. 1862;2016:860–868. - PMC - PubMed

[3] Iadecola C, Duering M, Hachinski V, Joutel A, Pendlebury ST, Schneider JA, Dichgans M. Vascular cognitive impairment and dementia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2019;73:3326–3344. - PMC - PubMed

[4] Iadecola C, Duering M, Hachinski V, Joutel A, Pendlebury ST, Schneider JA, Dichgans M. Vascular cognitive impairment and dementia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2019;73:3326–3344. - PMC - PubMed

[5] Zlokovic BV, Gottesman RF, Bernstein KE, Seshadri S, McKee A, Snyder H, Greenberg SM, Yaffe K, Schaffer CB, Yuan C, Hughes TM, Daemen MJ, Williamson JD, Gonzalez HM, Schneider J, Wellington CL, Katusic ZS, Stoeckel L, Koenig JI, Corriveau RA, Fine L, Galis ZS, Reis J, Wright JD and Chen J. Vascular contributions to cognitive impairment and dementia (VCID): a report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop. Alzheimers Dement. 2020. - PubMed

[6] Zlokovic BV, Gottesman RF, Bernstein KE, Seshadri S, McKee A, Snyder H, Greenberg SM, Yaffe K, Schaffer CB, Yuan C, Hughes TM, Daemen MJ, Williamson JD, Gonzalez HM, Schneider J, Wellington CL, Katusic ZS, Stoeckel L, Koenig JI, Corriveau RA, Fine L, Galis ZS, Reis J, Wright JD and Chen J. Vascular contributions to cognitive impairment and dementia (VCID): a report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop. Alzheimers Dement. 2020. - PubMed

[7] Toth P, Tarantini S, Csiszar A, Ungvari Z. Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol. 2017;312:H1–H20. - PMC - PubMed

[8] Toth P, Tarantini S, Csiszar A, Ungvari Z. Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol. 2017;312:H1–H20. - PMC - PubMed

[9] Tarantini S, Tran CHT, Gordon GR, Ungvari Z, Csiszar A. Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol. 2017;94:52–58. - PMC - PubMed

[10] Tarantini S, Tran CHT, Gordon GR, Ungvari Z, Csiszar A. Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol. 2017;94:52–58. - PMC - PubMed

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

Affiliations

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

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Conflict of interest statement

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