Hayashi K, Nakamura S, Morishita R, Moriguchi A, Aoki M, Matsumoto K, Nakamura T, Kaneda Y, Sakai N, Ogihara T
Division of Gene Therapy Science, Osaka University Medical School, Japan.
Gene Ther. 2000 Oct;7(19):1664-71. doi: 10.1038/sj.gt.3301284.
Although most therapeutic strategies to prevent restenosis are designed to inhibit vascular smooth muscle cell (VSMC) proliferation directly, VSMC proliferation might be indirectly inhibited by re-endothelialization, as endothelial cells secrete antiproliferative and antithrombotic substances. We hypothesized that application of an endothelium-specific growth factor to balloon-injured arteries could accelerate re-endothelialization, thereby attenuating intimal hyperplasia. In this study, we investigated in vivo gene transfer of human HGF that exclusively stimulated endothelial cells without replication of VSMC growth into injured vessels. Transfection of human HGF gene into rat balloon-injured carotid artery resulted in significant inhibition of neointimal formation up to at least 8 weeks after transfection, accompanied by detection of human immunoreactive HGF. Induction of re-endothelialization induced by overexpression of human HGF gene transfer into balloon-injured vessels is supported by several lines of evidence: (1) Administration of HGF vector. but not control vector, markedly inhibited neointimal formation, accompanied by a significant increase in vascular human and rat HGF concentrations. (2) Planimetric analysis demonstrated a significant increase in re-endothelialized area in arteries transfected with human HGF vector. (3) Induction of NO content in balloon-injured vessels transfected with human HGF vector was observed in accordance with the recovery of endothelial vasodilator properties in response to acetylcholine. As endogenous HGF expression in balloon-injured vessels was significantly decreased as compared with normal vessels, the present study demonstrated the successful inhibition of neointimal formation by transfection of human HGF gene as 'cytokine supplement therapy' in a rat balloon injury model.
尽管大多数预防再狭窄的治疗策略旨在直接抑制血管平滑肌细胞（VSMC）增殖，但由于内皮细胞分泌抗增殖和抗血栓形成物质，再内皮化可能间接抑制VSMC增殖。我们假设将内皮特异性生长因子应用于球囊损伤的动脉可加速再内皮化，从而减轻内膜增生。在本研究中，我们研究了人HGF的体内基因转移，该因子专门刺激内皮细胞而不引起VSMC生长复制进入受损血管。将人HGF基因转染到大鼠球囊损伤的颈动脉中，导致转染后至少8周内膜形成受到显著抑制，并伴有人免疫反应性HGF的检测。几条证据支持人HGF基因转移过表达诱导球囊损伤血管再内皮化：（1）给予HGF载体而非对照载体，显著抑制内膜形成，同时血管中人及大鼠HGF浓度显著增加。（2）平面分析表明，转染人HGF载体的动脉中再内皮化面积显著增加。（3）观察到转染人HGF载体的球囊损伤血管中NO含量增加，这与对乙酰胆碱的内皮舒张特性恢复一致。由于与正常血管相比，球囊损伤血管中内源性HGF表达显著降低，但本研究证明在大鼠球囊损伤模型中，通过转染人HGF基因作为“细胞因子补充疗法”成功抑制了内膜形成。
