Hiltunen M O, Laitinen M, Turunen M P, Jeltsch M, Hartikainen J, Rissanen T T, Laukkanen J, Niemi M, Kossila M, Häkkinen T P, Kivelä A, Enholm B, Mansukoski H, Turunen A M, Alitalo K, Ylä-Herttuala S
A.I. Virtanen Institute, University of Kuopio, Kuopio, Finland.
Circulation. 2000 Oct 31;102(18):2262-8. doi: 10.1161/01.cir.102.18.2262.
Gene transfer to the vessel wall may provide new possibilities for the treatment of vascular disorders, such as postangioplasty restenosis. In this study, we analyzed the effects of adenovirus-mediated vascular endothelial growth factor (VEGF)-C gene transfer on neointima formation after endothelial denudation in rabbits. For comparison, a second group was treated with VEGF-A adenovirus and a third group with lacZ adenovirus. Clinical-grade adenoviruses were used for the study.
Aortas of cholesterol-fed New Zealand White rabbits were balloon-denuded, and gene transfer was performed 3 days later. Animals were euthanized 2 and 4 weeks after the gene transfer, and intima/media ratio (I/M), histology, and cell proliferation were analyzed. Two weeks after the gene transfer, I/M in the lacZ-transfected control group was 0. 57+/-0.04. VEGF-C gene transfer reduced I/M to 0.38+/-0.02 (P:<0.05 versus lacZ group). I/M in VEGF-A-treated animals was 0.49+/-0.17 (P:=NS). The tendency that both VEGF groups had smaller I/M persisted at the 4-week time point, when the lacZ group had an I/M of 0.73+/-0.16, the VEGF-C group 0.44+/-0.14, and the VEGF-A group 0. 63+/-0.21 (P:=NS). Expression of VEGF receptors 1, 2, and 3 was detected in the vessel wall by immunocytochemistry and in situ hybridization. As an additional control, the effect of adenovirus on cell proliferation was analyzed by performing gene transfer to intact aorta without endothelial denudation. No differences were seen in smooth muscle cell proliferation or I/M between lacZ adenovirus and 0.9% saline-treated animals.
Adenovirus-mediated VEGF-C gene transfer may be useful for the treatment of postangioplasty restenosis and vessel wall thickening after vascular manipulations.
基因转移至血管壁可能为治疗血管疾病，如血管成形术后再狭窄提供新的途径。在本研究中，我们分析了腺病毒介导的血管内皮生长因子（VEGF）-C基因转移对兔内皮剥脱术后新生内膜形成的影响。作为对照，第二组用VEGF-A腺病毒处理，第三组用lacZ腺病毒处理。本研究使用临床级腺病毒。
给新西兰白兔喂食胆固醇后，对其主动脉进行球囊剥脱，3天后进行基因转移。基因转移后2周和4周对动物实施安乐死，并分析内膜/中膜比值（I/M）、组织学和细胞增殖情况。基因转移后2周，lacZ转染对照组的I/M为0.57±0.04。VEGF-C基因转移使I/M降至0.38±0.02（与lacZ组相比，P<0.05）。VEGF-A处理动物的I/M为0.49±0.17（P=无显著性差异）。在4周时间点，两个VEGF组I/M较小的趋势仍然存在，此时lacZ组的I/M为0.73±0.16，VEGF-C组为0.44±0.14，VEGF-A组为0.63±0.21（P=无显著性差异）。通过免疫细胞化学和原位杂交在血管壁中检测到VEGF受体1、2和3的表达。作为额外对照，通过对未进行内皮剥脱的完整主动脉进行基因转移，分析腺病毒对细胞增殖的影响。在lacZ腺病毒处理的动物和0.9%盐水处理的动物之间，平滑肌细胞增殖或I/M未见差异。
腺病毒介导的VEGF-C基因转移可能有助于治疗血管成形术后再狭窄和血管操作后的血管壁增厚。
