Recombinant adeno-associated viral vector encoding human VEGF165 induces neomicrovessel formation in the adult mouse brain
Recombinant adeno-associated viral vector encoding human VEGF165 induces neomicrovessel formation in the adult mouse brain
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DOI：
10.2741/2042
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发表时间：
2006-09-01
影响因子：
3.1
通讯作者：
Yang, Guo-Yuan
中科院分区：
文献类型：
--
作者：
Shen, Fanxia;Su, Hua;Yang, Guo-Yuan
治疗性基因的传递代表了一种迷人的可能性，可以加速组织中难以治疗的损伤修复过程，如脑缺血。目前的研究表明，基因转移诱导的局部脑血管生成可能提供一个重要的治疗策略。在本研究中，我们报道了用腺相关病毒（AAV）载体表达血管内皮生长因子（VEGF 165）的165个氨基酸亚型诱导血管生成的功效。我们发现AAV血清型1比AAV血清型2具有更高的脑组织转导效率。定量血管计数显示，与对照组相比，AAV-VEGF转导的小鼠中的微血管从1周至12周显著增加（AAV-VEGF：316 +/-58 vs. AAV-lacZ：180 +/-34和盐水：152 +/-35血管/mm（2），在6周时，p < 0.05）。增殖细胞核抗原（PCNA）染色证实这些微血管增殖活跃。荧光双标染色结果显示，AAV-VEGF基因转染后，神经元、星形胶质细胞和内皮细胞均可表达VEGF。AAV载体没有引起可检测的炎症反应、细胞损失或神经元损伤。我们的数据强调了血管生成在脑组织中的重要性，并表明VEGF基因转移可能是治疗脑缺血性疾病的一种有价值的方法。
Delivery of therapeutic genes represents a fascinating possibility to accelerate injury-repairing process in tissues that are otherwise difficult to treat, such as cerebral ischemia. Current studies indicate that gene transfer-induced focal angiogenesis in the brain may provide an important therapeutic strategy. In the present study, we reported the efficacy of induction of angiogenesis with an adeno-associated virus (AAV) vector expressing the 165 amino acid isoform of vascular endothelial growth factor (VEGF165). We found AAV serotype 1 has more efficiency in transduction of the brain tissue than AAV serotype 2. Quantitative vessel counting showed that microvessels in AAV-VEGF transduced mice significantly increased from 1 week up to 12 weeks compared to the control groups (AAV-VEGF: 316 +/- 58 vs. AAV-lacZ: 180 +/- 34 and saline: 152 +/- 35 vessels/mm(2), at 6 weeks, p < 0.05). Proliferating cell nuclear antigen (PCNA) staining confirmed these microvessels were actively proliferating. Double-labeled fluorescence staining demonstrated that neurons, astrocytes, and endothelial cells could express VEGF following AAV-VEGF gene transfer. AAV vectors did not elicit a detectable inflammatory response, cell loss or neuronal damage. Our data underline the importance of angiogenesis in the brain tissue and indicate that VEGF gene transfer might present a valuable approach to treat brain ischemic disorders.