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Insulin-Independent and Dependent Glucose Transporters in Brain Mural Cells in CADASIL

Lookup NU author(s): Dr Yoshiki HaseORCiD, Professor Raj Kalaria



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© Copyright © 2020 Panahi, Rodriguez, Fereshtehnejad, Arafa, Bogdanovic, Winblad, Cedazo-Minguez, Rinne, Darreh-Shori, Hase, Kalaria, Viitanen and Behbahani.Typical cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the human NOTCH3 gene. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy is characterized by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small vessels. Blood regulating vascular smooth muscle cells (VSMCs) appear as the key target in CADASIL but the pathogenic mechanisms remain unclear. With the hypothesis that brain glucose metabolism is disrupted in VSMCs in CADASIL, we investigated post-mortem tissues and VSMCs derived from CADASIL patients to explore gene expression and protein immunoreactivity of glucose transporters (GLUTs), particularly GLUT4 and GLUT2 using quantitative RT-PCR and immunohistochemical techniques. In vitro cell model analysis indicated that both GLUT4 and -2 gene expression levels were down-regulated in VSMCs derived from CADASIL patients, compared to controls. In vitro studies further indicated that the down regulation of GLUT4 coincided with impaired glucose uptake in VSMCs, which could be partially rescued by insulin treatment. Our observations on reduction in GLUTs in VSMCs are consistent with previous findings of decreased cerebral blood flow and glucose uptake in CADASIL patients. That impaired ability of glucose uptake is rescued by insulin is also consistent with previously reported lower proliferation rates of VSMCs derived from CADASIL subjects. Overall, these observations are consistent with the development of severe cerebral arteriopathy in CADASIL, in which VSMCs are replaced by widespread fibrosis.

Publication metadata

Author(s): Panahi M, Rodriguez PR, Fereshtehnejad S-M, Arafa D, Bogdanovic N, Winblad B, Cedazo-Minguez A, Rinne J, Darreh-Shori T, Hase Y, Kalaria RN, Viitanen M, Behbahani H

Publication type: Article

Publication status: Published

Journal: Frontiers in Genetics

Year: 2020

Volume: 11

Print publication date: 01/09/2020

Online publication date: 15/09/2020

Acceptance date: 10/08/2020

Date deposited: 13/01/2021

ISSN (electronic): 1664-8021

Publisher: Frontiers Media S.A.


DOI: 10.3389/fgene.2020.01022


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Funder referenceFunder name
... [RK] Newcastle Centre for Brain Ageing and Vitality (BBSRC, EPSRC, ESRC and MRC, LLHW), ...
... award to the Newcastle upon Tyne Hospitals NHS Foundation Trust, and a grant from the Alzheimer’s Society and ART as part of the Brains for Dementia Research Project.
... with further support from the Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases ...
...[RK] and Alzheimer’s Research (ARUK). The NBTR is funded by a grant from the UK MRC (G0400074) ...
RK’s work was supported by grants from the UK Medical Research Council (MRC, G0500247) ...