A major obstacle in inducing therapeutic angiogenesis in the heart is inefficient gene transfer to endothelial cells (ECs). Here, we identify compounds able to enhance the permissiveness of cardiac ECs to adeno-associated virus (AAV) vectors, which stand as ideal tools for in vivo gene delivery. We screened a library of >1,500 US Food and Drug Administration (FDA)-approved drugs, in combination with AAV vectors, in cardiac ECs. Among the top drugs increasing AAV-mediated transduction, we found vatalanib, an inhibitor of multiple tyrosine kinase receptors. The increased AAV transduction efficiency by vatalanib was paralleled by induction of the endothelial-to-mesenchymal transition, as documented by decreased endothelial and increased mesenchymal marker expression. Induction of the endothelial-to-mesenchymal transition by other strategies similarly increased EC permissiveness to AAV vectors. In vivo injection of AAV vectors in the heart after myocardial infarction resulted in the selective transduction of cells undergoing the endothelial-to-mesenchymal transition, which is known to happen transiently after cardiac ischemia. Collectively, these results point to the endothelial-to-mesenchymal transition as a mechanism for improving AAV transduction in cardiac ECs, with implications for both basic research and the induction of therapeutic angiogenesis in the heart.

中文翻译：

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内皮-间充质转化增强了心脏内皮细胞对 AAV 载体的允许性


在心脏中诱导治疗性血管生成的一个主要障碍是基因向内皮细胞 （EC） 的低效转移。在这里，我们确定了能够增强心脏 ECs 对腺相关病毒 （AAV） 载体的允许性的化合物，这是体内基因递送的理想工具 。我们在心脏 EC 中筛选了 >1,500 种美国食品和药物管理局 （FDA） 批准的药物库，并与 AAV 载体联合使用。在增加 AAV 介导的转导的主要药物中，我们发现了 vatalanib，一种多种酪氨酸激酶受体的抑制剂。vatalanib 增加的 AAV 转导效率与诱导内皮到间充质转化平行，如内皮细胞表达降低和间充质标志物表达增加所证明的那样。其他策略诱导内皮-间充质转化同样增加了 EC 对 AAV 载体的允许性。 心肌梗死后在心脏中体内注射 AAV 载体导致经历内皮到间充质转变的细胞选择性转导，已知这在心肌缺血后短暂发生。总的来说，这些结果表明，内皮到间充质转化是改善心脏内皮细胞中 AAV 转导的一种机制，对基础研究和心脏治疗性血管生成的诱导都有影响。