Periadventitial atRA citrate-based polyester membranes reduce neointimal hyperplasia and restenosis after carotid injury in rats
Periadventitial atRA citrate-based polyester membranes reduce neointimal hyperplasia and restenosis after carotid injury in rats
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DOI：
10.1152/ajpheart.00914.2013
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发表时间：
2014-11-15
影响因子：
4.8
通讯作者：
Kibbe, Melina R.
中科院分区：
文献类型：
--
作者：
Gregory, Elaine K.;Webb, Antonio R.;Kibbe, Melina R.
口服全反式视黄酸（atRA）已被证明可以减少新内膜增生的形成；然而，所需剂量是化疗剂量的30倍，并且已经有副作用报道。由于新内膜形成是一个局部过程，因此需要新的局部递送方法。本研究评估了基于柠檬酸盐的聚酯聚（1,8辛二醇柠檬酸酯）（POC）血管周围膜中的atRA是否可以预防动脉损伤后的新内膜增生。通过高效液相色谱和质谱检测制备了 atRA-POC 膜并表征了 atRA 释放。将大鼠外膜成纤维细胞（AF）和血管平滑肌细胞（VSMC）暴露于不同浓度的atRA；体外评估增殖、凋亡和坏死。采用大鼠颈动脉球囊损伤模型评价atRA-POC膜对体内新生内膜形成、细胞增殖、凋亡、巨噬细胞浸润和血管细胞粘附分子1（VCAM-1）表达的影响。 atRA-POC 膜在 2 周内释放了 12 微克 atRA，其中 92% 的释放发生在第一周。 24小时时，atRA（200μmol/l）抑制[H-3]-胸苷掺入AF和VSMC，分别达78%和72%（*P = 0.001），细胞凋亡或坏死可以忽略不计。组织形态计量学分析表明，atRA-POC 膜可抑制球囊损伤后的新内膜形成，内膜面积、内膜中膜面积比和狭窄百分比分别减少 56%、57% 和 50%（P = 0.001）。 atRA-POC 膜在 2 周时对细胞凋亡或增殖没有明显影响。关于生物相容性，我们发现使用 atRA-POC 膜处理的动物内膜层巨噬细胞浸润减少了 76%（P < 0.003），同时 VCAM-1 染色减少了 53%（P < 0.001）。总之，atRA 的血管周围递送抑制了新内膜形成和再狭窄。这些数据表明 atRA-POC 膜可能适合作为局部疗法来抑制开放性心血管手术后的新内膜增生。
Oral all-trans retinoic acid (atRA) has been shown to reduce the formation of neointimal hyperplasia; however, the dose required was 30 times the chemotherapeutic dose, which already has reported side effects. As neointimal formation is a localized process, new approaches to localized delivery are required. This study assessed whether atRA within a citrate-based polyester, poly(1,8 octanediolcitrate) (POC), perivascular membrane would prevent neointimal hyperplasia following arterial injury. atRA-POC membranes were prepared and characterized for atRA release via high-performance liquid chromatography with mass spectrometry detection. Rat adventitial fibroblasts (AF) and vascular smooth muscle cells (VSMC) were exposed to various concentrations of atRA; proliferation, apoptosis, and necrosis were assessed in vitro. The rat carotid artery balloon injury model was used to evaluate the impact of the atRA-POC membranes on neointimal formation, cell proliferation, apoptosis, macrophage infiltration, and vascular cell adhesion molecule 1 (VCAM-1) expression in vivo. atRA-POC membranes released 12 mu g of atRA over 2 wk, with 92% of the release occurring in the first week. At 24 h, atRA (200 mu mol/l) inhibited [H-3]-thymidine incorporation into AF and VSMC by 78% and 72%, respectively (*P = 0.001), with negligible apoptosis or necrosis. Histomorphometry analysis showed that atRA-POC membranes inhibited neointimal formation after balloon injury, with a 56%, 57%, and 50% decrease in the intimal area, intima-to-media area ratio, and percent stenosis, respectively (P = 0.001). atRA-POC membranes had no appreciable effect on apoptosis or proliferation at 2 wk. Regarding biocompatibility, we found a 76% decrease in macrophage infiltration in the intima layer (P < 0.003) in animals treated with atRA-POC membranes, with a coinciding 53% reduction in VCAM-1 staining (P < 0.001). In conclusion, perivascular delivery of atRA inhibited neointimal formation and restenosis. These data suggest that atRA-POC membranes may be suitable as localized therapy to inhibit neointimal hyperplasia following open cardiovascular procedures.