Experimental Study Of Estrogen Eluting Stent Inhibiting Neointima Formation

Background and Objective: Intracoronary stent placement has the ability to significantly lower the restenosis rate after percutaneous transluminal coronary angioplasty, but there are still relatively high restenosis rate (13%³0%) after stenting, so that restenosis has became the major limitation of the successful therapy of percutaneous coronary intervention (PCI) for patients with coronary artery disease. In recent years, anti-restenotic therapy has achieved a breakthrough with the development of drug-eluting stents. The immunosuppressive agent rapamycin and the antimitotic agent paclitaxel have been proposed as the most promising stent eluting agents by clinical application currently. However, there might be some potential problems, such as little selectivity of those agents for the target of VSMCs with damage on endothelial cells, which might cause delay of re-endothelialization then following late in stent thrombosis, and arterial wall necrosis with stent malapposition due to chronic exposure of toxicsubstances. Thus, an idealagent would exhibit specificity to the vessel intima, without having an effect on endothelial cells or medial VSMCs. The female hormone estrogen has been shown to inhibit intimal smooth muscle cell proliferation and migration in animal models. However, unlike antiproliferative agents such as rapamycin and paclitaxel, estrogen has been shown to accelerate reendothelialization in response to injury in experimental models. This suggest that estrogen may be well suited as a stent coating agent. The primary objective of the present study is to determine whether the 17β-E2 eluting stent can inhibit neointimal growth and accelerate reendothelialization in rabbits abdominal aorta. Finally, we seed to reveal the mechanism of those effects and provide theoretical fundamentals of clinical application. Methods (1) Male hyperlipemia rabbits were randomized to receive E₂ eluting metal stents, phosphorylcholine (PC) coated metal stents or bare metal stents implanted in abdominal aortas in the three groups. (2) Rabbits coronary angiography was performed before being killed at different time after stents implantation and luminal diameter within the stented segment was measured. (3) The phosphorylcholine polymer local delivery pharmacokinetics in vivo of 17β-E2 were measured by radioimmunoassay. (4) Sections of stent were taken out and made specimens, and stained with HE. Pathologic change of the arterial wall at different time after stents implanted was observed by microscopy. Lumen area, thickness and area of neointima at different time after stent implantation were measured by computer image analysis technique. (5)Immunohistochemistry was used to detect the positive rate of factor â…§ expression of the arterial intima at different time in order toassess re-endothelialization degree. (6) The expression of ERK protein was evaluated by the immunblotting technique and Immunohistochemistry. Results (1) Angiographyic follow-up showed no stent thrombosis and restenosis occurred in any groups. (2) 17P-E2 remained on the PC coated stent at 1 h, 12 h, 24 h, 48 h after operation were 8.91 ug, 4.76 ug, 2.19 ug and 0.81 ug respectively. (3) The neointima area had increased at 2 weeks after stent implantation, and the lumen loss rates were less than 50% at 12 weeks in three groups. At 12 weeks the neointima area reduced 36 % in E2 eluting stent group compared with that of bare metal stent group, but was no difference between PC coated and bare metal stent groups. The ratio of neointima area at the time of 2 week was compared with that of 12 week in each group, and the result showed that the E2 group had higher ratio than other two groups (0. 74 x 0.62 and 0. 64, respectively). (4) At 2 week the re-endothelialization rate in E2 eluting stent group was found obviously higher than PC coated stent and bare metal stent groups (78.4 + 5.3% vs 60.3 ±3.7% and 59.8 + 4.9%, P<0.01), and at 4 weeks after stent implantation nearly complete re-endothelialization were found in three groups. (5) ERK activities were rapidly induced after stent implantation in abdominal aortas, meanwhile 170-E2 eluted stents successfully inhibited ERK activities at 0.5 h, which led to a significant reduction in neointimal formation in treated animals.Conclusion Implantation of 17p-E2 eluted stents appears effective in inhibition intimal hyperplasia and safe in the rabbit model. This benefit effect are associated with accelerated of re-endothelialization of treated arteries and...