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Inhibition of VEGF Signaling Reduces Diabetes-Exacerbated Brain Swelling, but Not Infarct Size, in Large Cerebral Infarction in Mice

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Abstract

In light of repeated translational failures with preclinical neuroprotection-based strategies, this preclinical study reevaluates brain swelling as an important pathological event in diabetic stroke and investigates underlying mechanism of the comorbidity-enhanced brain edema formation. Type 2 (mild), type 1 (moderate), and mixed type 1/2 (severe) diabetic mice were subjected to transient focal ischemia. Infarct volume, brain swelling, and IgG extravasation were assessed at 3 days post-stroke. Expression of vascular endothelial growth factor (VEGF)-A, endothelial-specific molecule-1 (Esm1), and the VEGF receptor 2 (VEGFR2) was determined in the ischemic brain. Additionally, SU5416, a VEGFR2 inhibitor, was treated in the type 1/2 diabetic mice, and stroke outcomes were determined. All diabetic groups displayed bigger infarct volume and brain swelling compared to nondiabetic mice, and the increased swelling was disproportionately larger relative to infarct enlargement. Diabetic conditions significantly increased VEGF-A, Esm1, and VEGFR2 expressions in the ischemic brain compared to nondiabetic mice. Notably, in diabetic mice, VEGFR2 mRNA levels were positively correlated with brain swelling, but not with infarct volume. Treatment with SU5416 in diabetic mice significantly reduced brain swelling. The study shows that brain swelling is a predominant pathological event in diabetic stroke and that an underlying event for diabetes-enhanced brain swelling includes the activation of VEGF signaling. This study suggests consideration of stroke therapies aiming at primarily reducing brain swelling for subjects with diabetes.

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Funding

Research reported in this study was supported by the National Institute of Health awards, NINDS R01NS077897 (SC), R01NS095359-10 (SC), and the Burke Foundation (SC).

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Author notes

  1. Eunhee Kim

    Present address: Vivian L. Smith Department of Neurosurgery at University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

Authors and Affiliations

  1. Burke-Cornell Medical Research Institute, White Plains, NY, 10605, USA

    Eunhee Kim, Jiwon Yang, Keun Woo Park & Sunghee Cho

  2. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine at Burke Medical Research Institute, 785 Mamaroneck Ave, White Plains, NY, 10605, USA

    Eunhee Kim & Sunghee Cho

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  1. Eunhee Kim
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Contributions

Eunhee Kim generated diabetic mice, characterized, performed MCAO and molecular analyses, and wrote the manuscript; Jiwon Yang and Keun Woo Park contributed to molecular and biochemical assessment; and Sunghee Cho designed the study and wrote the manuscript.

Corresponding author

Correspondence to Sunghee Cho.

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Ethical Approval

This article does not contain any studies with human participants. The care and use of animals were followed by the ethical staindards of the Institutional Animal Care and Use Committee (IACUC) of Weill Cornell Medicine in accordance with the IACUC, National Institutes of Health, and ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines.

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The authors declare that they have no conflict of interest.

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Kim, E., Yang, J., Park, K.W. et al. Inhibition of VEGF Signaling Reduces Diabetes-Exacerbated Brain Swelling, but Not Infarct Size, in Large Cerebral Infarction in Mice. Transl. Stroke Res. 9, 540–548 (2018). https://doi.org/10.1007/s12975-017-0601-z

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  • DOI: https://doi.org/10.1007/s12975-017-0601-z

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