title: Early VEGF inhibition attenuates blood-brain barrier disruption in ischemic rat brains by regulating the expression of MMPs.
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.
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Affiliated Hospital of Binzhou Medical College, Binzhou, Shandong 256603, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Chen-Long
authors.initials: CL
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.
authors.forename: Ling-Chao
authors.initials: LC
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Rui-Yan
authors.initials: RY
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Yong-Li
authors.initials: YL
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Chuan-Lu
authors.initials: CL
authors.lastname: Jiang
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001929:Brain Edema / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000032:analysis*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000037:antagonists & inhibitors*
chemical_list: D057134:Antibodies, Neutralizing; D018696:Neuroprotective Agents; D042461:Vascular Endothelial Growth Factor A; D020782:Matrix Metalloproteinases