Early VEGF inhibition attenuates blood-brain barrier disruption in ischemic rat brains by regulating the expression of MMPs

Zhang,Hai‑Tao; Zhang,Ping; Gao,Yi; Li,Chen‑Long; Wang,Hong‑Jun; Chen,Ling‑Chao; Feng,Yan; Li,Rui‑Yan; Li,Yong‑Li; Jiang,Chuan‑Lu

doi:10.3892/mmr.2016.5974

Early VEGF inhibition attenuates blood-brain barrier disruption in ischemic rat brains by regulating the expression of MMPs

Authors:
- Hai‑Tao Zhang
- Ping Zhang
- Yi Gao
- Chen‑Long Li
- Hong‑Jun Wang
- Ling‑Chao Chen
- Yan Feng
- Rui‑Yan Li
- Yong‑Li Li
- Chuan‑Lu Jiang
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Affiliations: Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China, Department of Ophthalmology, Affiliated Hospital of Binzhou Medical College, Binzhou, Shandong 256603, P.R. China, Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
Published online on: November 29, 2016 https://doi.org/10.3892/mmr.2016.5974
Pages: 57-64
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Vascular endothelial growth factor (VEGF) inhibition has been demonstrated to be an effective strategy in preserving the integrity of the blood-brain barrier (BBB) in patients with acute ischemic stroke. Loss of the BBB is the key event associated with morbidity and mortality in these patients. However, the underlying mechanisms remain poorly understood. In the present study, the effects of VEGF inhibition and the possible mechanism that underlies acute cerebral ischemia in rats was investigated. Following the induction of transient middle cerebral artery occlusion for a 90‑min period, either an anti‑VEGF neutralizing antibody (RB‑222; 5 or 10 µg), or IgG (control), was administered by intracerebroventricular injection at 1 h following reperfusion. Functional outcomes, BBB leakage, brain edema, microvessel numbers and the relative protein levels of VEGF, matrix metalloproteinase (MMP)-2, MMP-9, occludin and collagen-IV were then determined using neurological assessments, Evans Blue staining, brain water content, CD31 staining and western blotting. Treatment with RB‑222 at a dose of 5 and 10 µg significantly improved neurological functional outcomes and diminished infarct size, BBB leakage and brain edema compared with the MCAO and IgG groups at 24 h following reperfusion; 10 µg RB‑222 was more effective than a 5 µg dose of the antibody. In addition, RB‑222 reduced the number of immature microvessels, which subsequently attenuated BBB permeability. RB‑222 significantly repressed VEGF expression as well as decreased MMP‑2 and MMP‑9 expression. However, it enhanced occludin and collagen‑IV levels in the ischemic rat brain compared with the MCAO and IgG groups. Taken together, the results indicate that early inhibition of VEGF may have significant potential against cerebral ischemia, partly by regulating the expression of MMPs.

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