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

Mahmod Panahi1, Patricia Rodriguez Rodriguez1, Seyed-Mohammad Fereshtehnejad2,3

  • 1Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.

Frontiers in Genetics
|October 26, 2020
PubMed

Insights

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) involves impaired glucose metabolism in vascular smooth muscle cells (VSMCs). Reduced glucose transporters (GLUTs) in VSMCs contribute to CADASIL pathology, impacting brain glucose uptake.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder caused by NOTCH3 gene mutations.
  • CADASIL is characterized by small vessel arteriopathy, leading to subcortical ischemic strokes and leukoencephalopathy.
  • Vascular smooth muscle cells (VSMCs) are implicated in CADASIL pathogenesis, but mechanisms of brain glucose metabolism disruption remain unclear.

Purpose of the Study:

  • To investigate the role of glucose transporters (GLUTs) in VSMCs from CADASIL patients.
  • To explore the hypothesis that brain glucose metabolism is disrupted in VSMCs in CADASIL.
  • To examine gene expression and protein levels of GLUT4 and GLUT2 in VSMCs.

Main Methods:

  • Quantitative RT-PCR and immunohistochemical techniques were used to analyze post-mortem tissues and VSMCs.
  • In vitro cell models of VSMCs derived from CADASIL patients and controls were employed.
  • Glucose uptake assays and insulin treatment were performed to assess VSMC function.

Main Results:

  • Down-regulation of GLUT4 and GLUT2 gene expression was observed in VSMCs from CADASIL patients compared to controls.
  • Reduced GLUT4 expression correlated with impaired glucose uptake in CADASIL VSMCs.
  • Insulin treatment partially rescued the impaired glucose uptake in these cells.

Conclusions:

  • Impaired glucose metabolism in VSMCs, due to reduced GLUTs, contributes to the cerebral arteriopathy seen in CADASIL.
  • These findings align with reduced cerebral blood flow and glucose uptake observed in CADASIL patients.
  • The results suggest a link between VSMC dysfunction, impaired glucose uptake, and the fibrotic changes characteristic of CADASIL.

Keywords:
CADASILGLUT2GLUT4VSMCsstroke

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