Gene Transfer of Human Prostacyclin Synthase Prevents Neointimal Formation After Carotid Balloon Injury in Rats

Abstract

Background and Purpose-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 (PGI 2 ) synthase (PGIS) was recently implicated in the pathological proliferation of vascular smooth muscle cells (VSMC) in vitro. Here, we investigated the effects of increased PGI 2 synthesis on the pathological proliferation of VSMCs. Methods-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 PGF 1␣ , a stable hydrolyzed metabolite of PGI 2 , the histological distribution of the immunoreactivity for human PGIS and the ratio of neointimal/medial area were analyzed. Results-In the analyses of 6-keto PGF 1␣ , 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 1.2Ϯ0.4 in the PGIS expression-vector transfected group, which was significantly smaller than that of the vehicle control group, 1.7Ϯ0.5; PϽ0.01. Conclusions-It was thus demonstrated that the gene transfer of human PGIS expression-vector into rat carotid arteriesresulted in the increased production of human PGI 2 in the vascular wall, the expression of human PGIS in the developing neointima and significantly inhibited the neointimal formation generated after balloon injury. (Stroke. 1999;30:419-426.)Key Words: carotid arteries Ⅲ genes Ⅲ prostacyclins Ⅲ stenosis Ⅲ rats T he principal contributor to the pathogenesis of cerebral and myocardial infarction is the developing atherosclerosis. The process of atherosclerosis involves a chronic inflammatory response to the injury in the arterial wall, leading to a dysfunction of endothelial cells, the migration and activation of macrophages, and the proliferation of vascular smooth-muscle cells (VSMC). 1 The complex of inflammatory and fibroproliferative processes is manifested as intimal hyperplasia or the formation of fibrous plaques. Similar inflammatory and proliferative processes in the vascular wall are thought to underlie the pathogenesis of restenosis after percutaneous transluminal angioplasty (PTA) and carotid endarterectomy (CE). [2][3][4][5][6] A neointima formation after balloon angioplasty involves a complex interaction between numerous growth-regulatory See Editorial Comment, page 426 molecules that promote the migration and proliferation of VSMC. 2 Possible neointima-generating molecules include thrombin, platelet-derived growth factor (PDGF), basic fibrob...

Augmented Cardiac Hypertrophy in Response to Pressure Overload in Mice Lacking the Prostaglandin I 2 Receptor

“…37 In agreement with this effect, PGI 2 analogues have long been used for the treatment of primary pulmonary hypertension. 38 Recently, a gene therapy using PGI 2 synthase gene transfection has been tested in rat models of cardiovascular diseases, such as pulmonary hypertension, 39 vascular remodeling, 40 and peripheral vascular occlusion, 41 and has been shown to be promising. Furthermore, the present study showed a novel role of IP in pressure overload-induced cardiac hypertrophy, emphasizing, along with previous reports, a potent therapeutic potential of PGI 2 for cardiovascular diseases.…”

Local Overexpression of Monocyte Chemoattractant Protein-1 at Vessel Wall Induces Infiltration of Macrophages and Formation of Atherosclerotic Lesion

“…The common carotid artery was filled with HVJ-liposomes through a small catheter inserted into the external carotid artery and incubated for 15 minutes, as previously described. 11 After incubation, the external carotid artery was ligated at the orifice. The blood flow to the common and internal carotid arteries was restored by releasing the clips, and the wound was closed.…”

Acceleration of wound healing by combined gene transfer of hepatocyte growth factor and prostacyclin synthase with Shima Jet

“…22 Overexpression of the PGIS gene inhibits growth of vascular smooth muscle cells (VSMC), and transfer of PGIS gene ameliorates pulmonary hypertension and prevents neointimal formation after carotid balloon injury in rats. [23][24][25] Co-transfer of HGF and PGIS genes in a murine ischemic limb model has been reported to increase the concentration of HGF protein and resulted in a significant increase in blood flow and capillary density compared with transfer of HGF gene alone. 26,27 Based on these results, we examined the effects of co-transfer of HGF and PGIS genes by the Shima Jet on wound healing in this study.…”