Bevacizumab attenuates VEGF-induced angiogenesis and vascular malformations in the adult mouse brain.
Bevacizumab attenuates VEGF-induced angiogenesis and vascular malformations in the adult mouse brain.
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DOI：
10.1161/strokeaha.111.647982
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发表时间：
2012-07
期刊：
影响因子：
8.3
通讯作者：
Young WL
中科院分区：
文献类型：
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作者：
Walker EJ;Su H;Shen F;Degos V;Amend G;Jun K;Young WL
血管内皮生长因子(VEGF)在脑动静脉畸形(BAVM)中的表达升高。我们通过Alk1基因局部缺失和人血管内皮细胞生长因子刺激，建立了成年小鼠bAVM模型。我们推测，一旦建立了异常的血管系统，就需要强直的血管内皮生长因子刺激来维持异常的表型，而贝伐单抗(阿瓦斯丁)可以降低血管密度，减弱异常的血管表型。将表达人血管内皮生长因子的腺相关病毒载体(AAV-VEGF)单独注射到野生型(WT)小鼠的脑内，或将表达Cre重组酶的腺病毒载体(Ad-Cre)注射到Alk12f/2f小鼠体内，诱导血管生成和bAVM。6周后，给予贝伐单抗或曲妥珠单抗(赫赛汀，贝伐单抗对照)。检测血管密度(Vd)、异型增生指数(DI)、血管细胞增殖和凋亡及人类免疫球蛋白(HgG)(n=6)。与曲妥珠单抗(15 mg/kg)相比，给予AAV-VEGF治疗的WT小鼠给予5、10和15 mg/kg贝伐单抗可减少局灶性VD(p<；0.05)；给予5 mg/kg贝伐单抗可减少血管细胞的增殖(p=0.04)，增加TUNEL阳性的血管细胞(p=0.03)。更重要的是，贝伐单抗(5 mg/kg)可降低bAVM模型中的VD(p=0.01)和DI(p=0.02)。贝伐单抗处理组小鼠血管生成灶的血管壁和实质内可检测到人免疫球蛋白G。我们提供的原则证据是，一旦异常的AVM血管形成，血管内皮生长因子拮抗剂可以减少发育不良的血管的数量，应该作为人类疾病的一种治疗策略进行进一步评估。
Vascular endothelial growth factor (VEGF) expression is elevated in human brain arteriovenous malformations (bAVM). We have developed a bAVM model in the adult mouse by focal Alk1 gene deletion and human VEGF stimulation. We hypothesized that once the abnormal vasculature has been established; tonic VEGF stimulation is necessary to maintain the abnormal phenotype and VEGF antagonism by bevacizumab (Avastin) would reduce vessel density and attenuate the dysplastic vascular phenotype. Angiogenesis and bAVM were induced by injection of adeno-associated viral vector expressing human VEGF (AAV-VEGF) alone into the brain of wild-type (WT) mice or with adenoviral vector expressing Cre recombinase (Ad-Cre) into Alk12f/2fmice. Six weeks later, bevacizumab or trastuzumab (Herceptin, bevacizumab control) were administered. Vessel density (VD), dysplasia index (DI), vascular cell proliferation and apoptosis, and human IgG were assessed (n=6/group). Compared to trastuzumab (15 mg/kg), administration of 5, 10 and 15 mg/kg of bevacizumab to AAV-VEGF treated WT mice reduced focal VD (p<0.05); administration of 5 mg/kg bevacizumab decreased proliferating vascular cells (p=0.04) and increased TUNEL-positive vascular cells (p=0.03). More importantly, bevacizumab (5 mg/kg) treatment reduced both VD (p=0.01) and DI (p=0.02) in our bAVM model. Human IgG was detected in the vessel wall and the parenchyma in the angiogenic foci of bevacizumab treated mice. We provide proof-of-principle that, once abnormal AVM vessels have formed, VEGF antagonism may reduce the number of dysplastic vessels and should be further evaluated as a therapeutic strategy for the human disease.