Hypertonic saline downregulates endothelial cell-derived VEGF expression and reduces blood-brain barrier permeability induced by cerebral ischaemia via the VEGFR2/eNOS pathway

Wang,Qiaosheng; Deng,Yiyu; Huang,Linqiang; Zeng,Wenxin; Chen,Shenglong; Lv,Bo; Jiang,Wenqiang; Han,Yongli; Ding,Hongguang; Wen,Miaoyun; Zeng,Hongke

doi:10.3892/ijmm.2019.4262

Hypertonic saline downregulates endothelial cell-derived VEGF expression and reduces blood-brain barrier permeability induced by cerebral ischaemia via the VEGFR2/eNOS pathway

Authors:
- Qiaosheng Wang
- Yiyu Deng
- Linqiang Huang
- Wenxin Zeng
- Shenglong Chen
- Bo Lv
- Wenqiang Jiang
- Yongli Han
- Hongguang Ding
- Miaoyun Wen
- Hongke Zeng
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Affiliations: The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China
Published online on: July 2, 2019 https://doi.org/10.3892/ijmm.2019.4262
Pages: 1078-1090
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to explore the possible mechanisms by which hypertonic saline (HS) effectively ameliorates cerebral oedema via the vascular endothelial growth factor receptor 2 (VEGFR2)‑mediated endothelial nitric oxide synthase (eNOS) pathway of endothelial cells in rats. A middle cerebral artery occlusion (MCAO) model in Sprague‑Dawley rats and an oxygen‑glucose deprivation (OGD) model in cells were used in the present study. Evans blue (EB) staining and a horseradish peroxidase flux assay were performed to evaluate the protective effect of 10% HS on the blood‑brain barrier (BBB). The expression levels of vascular endothelial growth factor (VEGF), VEGFR2, zonula occludens 1 (ZO1) and occludin were quantified. The results demonstrated that 10% HS effectively reduced EB extravasation in the peri‑ischaemic brain tissue. At 24 h after MCAO, the protein expression levels of VEGF and VEGFR2 in the peri‑ischaemic brain tissue were downregulated following treatment with 10% HS. In vitro experiments demonstrated that the permeability of a monolayer endothelial cell barrier was decreased significantly following HS treatment. In addition, VEGF and VEGFR2 protein expression levels were increased in endothelial cells under hypoxic conditions, but that effect was suppressed by HS treatment. Furthermore, HS inhibited the downregulation of ZO1 and occludin effectively, possibly through the VEGFR2/phospholipase C γ1 (PLCγ1)/eNOS signalling pathway. In conclusion, 10% HS may alleviate cerebral oedema through reducing ischaemia‑induced BBB permeability, as a consequence of inhibiting VEGFR2/PLCγ1/eNOS‑mediated downregulation of ZO1 and occludin.

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