Early VEGF inhibition attenuates blood-brain barrier disruption in ischemic rat brains by regulating the expression of MMPs.
Early VEGF inhibition attenuates blood-brain barrier disruption in ischemic rat brains by regulating the expression of MMPs.
复制标题
早期 VEGF 抑制通过调节 MMP 的表达来减轻缺血大鼠大脑中血脑屏障的破坏
DOI：
10.3892/mmr.2016.5974
复制
发表时间：
2017-01
影响因子：
3.4
通讯作者：
Jiang CL
中科院分区：
文献类型：
--
作者：
Zhang HT;Zhang P;Gao Y;Li CL;Wang HJ;Chen LC;Feng Y;Li RY;Li YL;Jiang CL
血管内皮生长因子（VEGF）抑制已被证明是一种有效的策略，在保持血脑屏障（BBB）的完整性，急性缺血性中风患者。BBB丧失是与这些患者的发病率和死亡率相关的关键事件。然而，对潜在的机制仍然知之甚少。在本研究中，VEGF抑制的影响和可能的机制，急性脑缺血大鼠进行了调查。在诱导短暂性大脑中动脉闭塞90分钟后，在再灌注后1小时通过脑室内注射给予抗VEGF中和抗体（RB-222; 5或10 μg）或IgG（对照）。然后通过神经功能评估、伊文思蓝染色、脑含水量、CD 31染色和蛋白质印迹法测定功能结局、BBB渗漏、脑水肿、微血管数目和VEGF、基质金属蛋白酶（MMP）-2、MMP-9、occludin和胶原-IV的相对蛋白水平。在再灌注后24小时，与MCAO和IgG组相比，5和10 µg剂量的RB-222治疗显著改善了神经功能结局，并减少了梗死面积、BBB渗漏和脑水肿; 10 µg RB-222比5 µg剂量的抗体更有效。此外，RB-222减少了未成熟微血管的数量，从而减弱了BBB的通透性。RB-222显著抑制VEGF表达以及降低MMP-2和MMP-9表达。然而，与MCAO和IgG组相比，它增强了缺血大鼠脑中occludin和胶原IV的水平。总之，结果表明，VEGF的早期抑制可能具有显著的抗脑缺血的潜力，部分通过调节MMPs的表达。
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.