Todaka T, Yokoyama C, Yanamoto H, Hashimoto N, Nagata I, Tsukahara T, Hara S, Hatae T, Morishita R, Aoki M, Ogihara T, Kaneda Y, Tanabe T
Department of Cerebrovascular Surgery, Laboratory for Cerebrovascular Disorders, National Cardio-Vascular Center, Osaka University Medical Center, Osaka, Japan.
Stroke. 1999 Feb;30(2):419-26. doi: 10.1161/01.str.30.2.419.
A disordered proliferative process in the vascular wall is thought to underlie the pathogenesis of restenosis after percutaneous transluminal angioplasty and carotid endarterectomy. A growth inhibitory property of overexpressed prostacyclin (PGI2) synthase (PGIS) was recently implicated in the pathological proliferation of vascular smooth muscle cells (VSMC) in vitro. Here, we investigated the effects of increased PGI2 synthesis on the pathological proliferation of VSMCs.
The cDNA encoding human PGIS was transfected into endothelium-denuded rat carotid arteries after arterial balloon injury with the use of hemagglutinating virus Japan (HVJ). HVJ liposome vector complex without PGIS cDNA was used for vehicle control. The level of 6-keto PGF1alpha, a stable hydrolyzed metabolite of PGI2, the histological distribution of the immunoreactivity for human PGIS and the ratio of neointimal/medial area were analyzed.
In the analyses of 6-keto PGF1alpha, the level in the carotid arteries was significantly elevated 3 days after PGIS expression-vector transfection compared with that in the arteries after vehicle transfection. Seven days after human PGIS expression-vector transfection, the PGIS cDNA-transfected neointimal cells were strongly positive for human PGIS immunoreactivity in 81% sections examined. Fourteen days after the injury, the ratio of neointimal/medial area was 1.2+/-0.4 in the PGIS expression-vector transfected group, which was significantly smaller than that of the vehicle control group, 1.7+/-0.5; P<0.01.
It was thus demonstrated that the gene transfer of human PGIS expression-vector into rat carotid arteries resulted in the increased production of human PGI2 in the vascular wall, the expression of human PGIS in the developing neointima and significantly inhibited the neointimal formation generated after balloon injury.
血管壁中紊乱的增殖过程被认为是经皮腔内血管成形术和颈动脉内膜切除术后再狭窄发病机制的基础。最近发现，过表达的前列环素（PGI2）合酶（PGIS）具有生长抑制特性，参与体外血管平滑肌细胞（VSMC）的病理性增殖。在此，我们研究了增加PGI2合成对VSMC病理性增殖的影响。
使用日本血凝病毒（HVJ）将编码人PGIS的cDNA转染至动脉球囊损伤后的去内皮大鼠颈动脉。不含PGIS cDNA的HVJ脂质体载体复合物用作载体对照。分析了PGI2的稳定水解代谢产物6-酮-PGF1α的水平、人PGIS免疫反应性的组织学分布以及新生内膜/中膜面积比。
在6-酮-PGF1α分析中，与载体转染后的动脉相比，PGIS表达载体转染后3天颈动脉中的水平显著升高。人PGIS表达载体转染7天后，在81%的检查切片中，PGIS cDNA转染的新生内膜细胞中人PGIS免疫反应性呈强阳性。损伤后14天，PGIS表达载体转染组的新生内膜/中膜面积比为1.2±0.4，显著小于载体对照组的1.7±0.5；P<0.01。
因此证明，将人PGIS表达载体基因转移至大鼠颈动脉可导致血管壁中人PGI2产生增加，在发育中的新生内膜中人PGIS表达，并显著抑制球囊损伤后产生的新生内膜形成。
