Leppänen Olli, Rutanen Juha, Hiltunen Mikko O, Rissanen Tuomas T, Turunen Mikko P, Sjöblom Tobias, Brüggen Josef, Bäckström Gudrun, Carlsson Marianne, Buchdunger Elisabeth, Bergqvist David, Alitalo Kari, Heldin Carl-Henrik, Ostman Arne, Ylä-Herttuala Seppo
Ludwig Institute for Cancer Research, Uppsala, Sweden.
Circulation. 2004 Mar 9;109(9):1140-6. doi: 10.1161/01.CIR.0000117234.08626.7C. Epub 2004 Feb 9.
Platelet-derived growth factor (PDGF) antagonists have demonstrated beneficial effects on neointima formation, but in studies using PDGF inhibitors and extended follow-up, the lesions reoccur. These findings implicate a need to combine targeting of PDGF with other strategies. Stimulation of reendothelialization by treatment with endothelial cell mitogens of the vascular endothelial growth factor (VEGF) family counteracts restenosis, but there are also concerns regarding the durability of the effect with this approach.
To explore whether a combined use of PDGF antagonist and stimulation of reendothelialization confers better results than each therapy alone, we combined systemic administration of imatinib mesylate (STI571/Gleevec, 10 mg/kg(-1) per d(-1)), a tyrosine kinase inhibitor with activity against PDGF receptors, with local intravascular adenovirus-mediated VEGF-C gene transfer (1.15x10(10) pfu) in cholesterol-fed, balloon-injured rabbits. Throughout the course of the STI571 therapy, the circulating concentrations were able to suppress PDGF receptor phosphorylation. At 3 weeks, the treatment with STI571 led to a transient decrease in intralesion macrophages and to an increase in intimal smooth muscle cell apoptosis. VEGF-C application reduced neointima formation and accelerated reendothelialization. However, none of the therapies alone reduced intimal thickening at a 6-week time point, whereas the combined treatment led to a persistent reduction (55% versus control) in lesion size at this time point.
Our study provides one of the first successful examples of gene therapy combined with a pharmacological treatment to modulate 2 distinct ligand-receptor signaling systems and suggests combination of local VEGF-C gene therapy with systemic inhibition of PDGF signaling as a novel principle to prevent intimal hyperplasia after vascular manipulations.
血小板衍生生长因子（PDGF）拮抗剂已显示出对新生内膜形成有有益作用，但在使用PDGF抑制剂并进行长期随访的研究中，病变会复发。这些发现表明需要将针对PDGF的靶向治疗与其他策略相结合。用血管内皮生长因子（VEGF）家族的内皮细胞促细胞分裂剂治疗刺激再内皮化可抵消再狭窄，但对于这种方法效果的持久性也存在担忧。
为了探究联合使用PDGF拮抗剂和刺激再内皮化是否比单独使用每种疗法能产生更好的效果，我们将甲磺酸伊马替尼（STI571/格列卫，每天10 mg/kg-1）（一种对PDGF受体有活性的酪氨酸激酶抑制剂）的全身给药与局部血管内腺病毒介导的VEGF-C基因转移（1.15×1010 pfu）相结合，应用于喂食胆固醇、球囊损伤的兔子。在整个STI571治疗过程中，循环浓度能够抑制PDGF受体磷酸化。在3周时，STI571治疗导致病变内巨噬细胞短暂减少，内膜平滑肌细胞凋亡增加。应用VEGF-C减少了新生内膜形成并加速了再内皮化。然而，在6周时间点，单独任何一种疗法都没有减少内膜增厚，而联合治疗在该时间点导致病变大小持续减少（与对照组相比减少55%）。
我们的研究提供了基因治疗与药物治疗相结合以调节两种不同配体-受体信号系统的首批成功范例之一，并表明局部VEGF-C基因治疗与系统性抑制PDGF信号相结合作为预防血管操作后内膜增生的新原则。
