Aflibercept, a VEGF (Vascular Endothelial Growth Factor)-Trap, Reduces Vascular Permeability and Stroke-Induced Brain Swelling in Obese Mice.
Aflibercept, a VEGF (Vascular Endothelial Growth Factor)-Trap, Reduces Vascular Permeability and Stroke-Induced Brain Swelling in Obese Mice.
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DOI：
10.1161/strokeaha.121.034362
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发表时间：
2021-08
期刊：
影响因子：
8.3
通讯作者：
Cho S
中科院分区：
文献类型：
--
作者：
Kim ID;Cave JW;Cho S
补充数字内容可在文本中找到。脑水肿是一个重要的潜在病理在急性中风，特别是当合并症存在。血管内皮生长因子（VEGF）信号与水肿有关。本研究探讨肥胖是否影响VEGF信号和脑水肿，以及VEGF抑制是否改变肥胖受试者的卒中结局。高脂肪饮食诱导的肥胖小鼠遭受短暂性大脑中动脉闭塞。在大脑中动脉闭塞3天后测量VEGF-A和VEGFR2（受体）表达、梗死体积和肿胀。为了验证抗VEGF策略的效果，我们在用rVEGF（重组VEGF； 50 ng/mL）刺激的人脐静脉内皮细胞中使用了aflibercept，这是一种具有VEGF结合结构域并作为诱饵受体的融合蛋白。在体内，肥胖小鼠在短暂性大脑中动脉闭塞30分钟后3小时给予阿非利西普（10 mg/kg）或IgG对照。通过IgG染色和右旋糖酐外渗评估脑缺血后血脑屏障完整性。另一组非肥胖（瘦）小鼠接受40分钟大脑中动脉闭塞，以测试阿布西普对恶性梗死的影响。与瘦小鼠相比，肥胖小鼠死亡率、梗死体积、肿胀和血脑屏障破坏增加。这些结果也与VEGF-A和VEGFR2表达增加有关。阿非利西普降低vegf - a刺激的人脐静脉内皮细胞的通透性和管状形成。与igg治疗的对照组相比，阿非利西普治疗的小鼠死亡率（40%对17%）、出血性转化（43%对27%）和脑肿胀（28%对18%）降低，尽管梗死面积相似。在患有严重中风的非肥胖小鼠中，阿布西普既没有改善也没有加剧中风的结果。研究表明，阿布西普选择性地减轻肥胖小鼠中风引起的脑水肿和血管通透性。这些发现表明，阿非利西普可用于减轻急性卒中中肥胖引起的脑水肿。
Supplemental Digital Content is available in the text. Brain edema is an important underlying pathology in acute stroke, especially when comorbidities are present. VEGF (Vascular endothelial growth factor) signaling is implicated in edema. This study investigated whether obesity impacts VEGF signaling and brain edema, as well as whether VEGF inhibition alters stroke outcome in obese subjects. High-fat diet-induced obese mice were subjected to a transient middle cerebral artery occlusion. VEGF-A and VEGFR2 (receptor) expression, infarct volume, and swelling were measured 3 days post-middle cerebral artery occlusion. To validate the effect of an anti-VEGF strategy, we used aflibercept, a fusion protein that has a VEGF-binding domain and acts as a decoy receptor, in human umbilical vein endothelial cells stimulated with rVEGF (recombinant VEGF; 50 ng/mL) for permeability and tube formation. In vivo, aflibercept (10 mg/kg) or IgG control was administered in obese mice 3 hours after transient 30 minutes middle cerebral artery occlusion. Blood-brain barrier integrity was assessed by IgG staining and dextran extravasation in the postischemic brain. A separate cohort of nonobese (lean) mice was subjected to 40 minutes middle cerebral artery occlusion to test the effect of aflibercept on malignant infarction. Compared with lean mice, obese mice had increased mortality, infarct volume, swelling, and blood-brain barrier disruption. These outcomes were also associated with increased VEGF-A and VEGFR2 expression. Aflibercept reduced VEGF-A-stimulated permeability and tube formation in human umbilical vein endothelial cells. Compared with the IgG-treated controls, mice treated with aflibercept had reduced mortality rates (40% versus 17%), hemorrhagic transformation (43% versus 27%), and brain swelling (28% versus 18%), although the infarct size was similar. In nonobese mice with large stroke, aflibercept neither improved nor exacerbated stroke outcomes. The study demonstrates that aflibercept selectively attenuates stroke-induced brain edema and vascular permeability in obese mice. These findings suggest the repurposing of aflibercept to reduce obesity-enhanced brain edema in acute stroke.