Laitinen M, Zachary I, Breier G, Pakkanen T, Häkkinen T, Luoma J, Abedi H, Risau W, Soma M, Laakso M, Martin J F, Ylä-Herttuala S
A.I. Virtanen Institute, University of Kuopio, Finland.
Hum Gene Ther. 1997 Oct 10;8(15):1737-44. doi: 10.1089/hum.1997.8.15-1737.
Thickening of the arterial intima and smooth muscle cell (SMC) proliferation remain major problems after vascular surgery and other types of vascular manipulations. We studied the effect of endothelial cell (EC)-specific vascular endothelial growth factor (VEGF) gene transfer on the thickening of the intima using a silicone collar inserted around carotid arteries that acted both as the agent that caused intimal SMC growth and as a reservoir for the transfected gene. The model preserved EC integrity and permitted direct extravascular gene transfer without any intravascular manipulation. Compared to beta-galactosidase (lacZ)-transfected control arteries, plasmid/liposome-mediated VEGF gene transfer significantly reduced intimal thickening 1 week after the gene transfer. Administration to the experimental animals of the nitric oxide (NO) synthase inhibitor L-NAME abolished the difference in intimal thickening between VEGF and lacZ-transfected arteries. Furthermore, VEGF caused NO release from cultured human umbilical vein EC. It is concluded that extravascular VEGF gene transfer attenuates intimal growth and could be useful for the prevention of intimal thickening during vascular surgery. Our results further suggest that VEGF may reduce SMC proliferation via a mechanism that involves VEGF-induced NO production from the endothelium.
动脉内膜增厚和平滑肌细胞（SMC）增殖仍是血管手术及其他类型血管操作后存在的主要问题。我们利用插入颈动脉周围的硅胶套研究了内皮细胞（EC）特异性血管内皮生长因子（VEGF）基因转移对内膜增厚的影响，该硅胶套既是引起内膜SMC生长的因素，又是转染基因的储存库。该模型保留了EC的完整性，并允许在无任何血管内操作的情况下进行直接血管外基因转移。与β-半乳糖苷酶（lacZ）转染的对照动脉相比，质粒/脂质体介导的VEGF基因转移在基因转移后1周显著减少了内膜增厚。给实验动物施用一氧化氮（NO）合酶抑制剂L-NAME消除了VEGF和lacZ转染动脉在内膜增厚方面的差异。此外，VEGF可使培养的人脐静脉EC释放NO。结论是血管外VEGF基因转移可减轻内膜生长，可能有助于预防血管手术期间的内膜增厚。我们的结果进一步表明，VEGF可能通过一种涉及VEGF诱导内皮细胞产生NO的机制来减少SMC增殖。
