Rissanen Tuomas T, Markkanen Johanna E, Arve Katja, Rutanen Juha, Kettunen Mikko I, Vajanto Ismo, Jauhiainen Suvi, Cashion Linda, Gruchala Marcin, Närvänen Outi, Taipale Pekka, Kauppinen Risto A, Rubanyi Gabor M, Ylä-Herttuala Seppo
Department of Molecular Medicine, A.I. Virtanen Institute, Kuopio University, Finland.
FASEB J. 2003 Jan;17(1):100-2. doi: 10.1096/fj.02-0377fje. Epub 2002 Nov 15.
Previous studies have shown that fibroblast growth factor (FGF)-1, FGF-2, and FGF-5 induce therapeutic angiogenesis. Here, we investigated the potential of FGF-4 for therapeutic neovascularization in comparison to vascular endothelial growth factor (VEGF), using adenoviral gene transfer in a novel rabbit hind limb ischemia model, with ischemia restricted to the calf. Magnetic resonance imaging and a modified Miles assay showed that both AdFGF-4 and AdVEGF given intramuscularly (i.m.) resulted in increases in vascular permeability and edema in transduced muscles 6 days after the gene transfer. In contrast, recombinant FGF-4 protein injected in the rabbit skin did not induce acute vascular permeability. Injections (i.m.) of AdFGF-4 and AdVEGF, but not intra-arterially administered AdVEGF, increased collateral growth, popliteal blood flow, and muscle perfusion compared with controls. The angiogenesis response consisted mainly of the enlargement of pre-existing vessels rather than an increase in capillary density. Adenoviral FGF-4 overexpression up-regulated endogenous VEGF, which may explain many of the effects thought to be specific for VEGF such as the increase in vascular permeability. This study demonstrates for the first time that FGF-4 induces vascular permeability, therapeutic angiogenesis, and arteriogenesis comparable to that of VEGF and could be useful for the treatment of peripheral vascular disease.
先前的研究表明，成纤维细胞生长因子（FGF）-1、FGF-2和FGF-5可诱导治疗性血管生成。在此，我们在一种新型兔后肢缺血模型中，利用腺病毒基因转移，将小腿作为缺血限制部位，研究了FGF-4与血管内皮生长因子（VEGF）相比在治疗性新生血管形成方面的潜力。磁共振成像和改良的迈尔斯试验显示，基因转移6天后，肌肉内（i.m.）注射AdFGF-4和AdVEGF均导致转导肌肉的血管通透性增加和水肿。相比之下，注射到兔皮肤中的重组FGF-4蛋白并未诱导急性血管通透性。与对照组相比，肌肉内注射AdFGF-4和AdVEGF可增加侧支生长、腘动脉血流量和肌肉灌注，但动脉内注射AdVEGF则无此效果。血管生成反应主要包括已有血管的扩张，而非毛细血管密度的增加。腺病毒介导的FGF-4过表达上调了内源性VEGF，这可能解释了许多被认为是VEGF特有的效应，如血管通透性增加。本研究首次证明，FGF-4可诱导与VEGF相当的血管通透性、治疗性血管生成和动脉生成，可能对治疗外周血管疾病有用。
