Reddy Maram K, Vasir Jaspreet K, Hegde Ganapati V, Joshi Shantaram S, Labhasetwar Vinod
Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
J Cardiovasc Pharmacol Ther. 2007 Sep;12(3):237-47. doi: 10.1177/1074248406297326.
A therapeutic strategy that would mitigate the events leading to hyperplasia and facilitate re-endothelialization of an injured artery after balloon angioplasty could be effective for a long-term patency of the artery. It is hypothesized that erythropoietin (EPO), which has both anti-inflammatory and antiapoptotic properties, will prevent hyperplasia, and its ability to proliferate and mobilize endothelial progenitor cells will re-endothelialize the injured artery. To test this hypothesis, EPO (5000 IU/kg) in solution was injected intraperitoneally 6 hours before vascular injury and then on every alternate day for a week or as a single dose (5000 IU/kg) in a sustained release gel formulation 1 week before the vascular injury. Morphometric analysis revealed nearly continuous re-endothelialization of the injured artery in EPO solution-treated animals (90% vs less than 20% in saline control); however, the treatment also caused excessive neointima formation (intima/media ratio, 2.10 +/- 0.09 vs 1.60 +/- 0.02 saline control, n = 5, P < .001). The EPO gel also induced similar excessive neointima formation. Immunohistochemical analysis of the injured arteries from the animals treated with EPO solution demonstrated a significant angiogenic response in adventitia and media, thus explaining the formation of excessive neointima. Although the results are in contrast to expectation, they explain a greater degree of stenosis seen in hemodialysis access fistulas in patients who are on EPO therapy for anemic condition. The results also caution the use of EPO, particularly in patients who are at a risk of vascular injury or are suffering from an atherosclerotic condition.
一种能够减轻导致增生的相关事件，并在球囊血管成形术后促进受损动脉重新内皮化的治疗策略，可能对动脉的长期通畅有效。据推测，具有抗炎和抗凋亡特性的促红细胞生成素（EPO）将预防增生，并且其增殖和动员内皮祖细胞的能力将使受损动脉重新内皮化。为了验证这一假设，在血管损伤前6小时腹腔注射溶解状态的EPO（5000 IU/kg），然后每隔一天注射一次，持续一周，或者在血管损伤前1周以缓释凝胶制剂形式单次注射（500 IU/kg）。形态计量学分析显示，EPO溶液处理的动物中受损动脉几乎持续重新内皮化（90%，而生理盐水对照组低于20%）；然而，该治疗也导致内膜过度增生（内膜/中膜比值，2.10±0.09，而生理盐水对照组为1.60±0.02，n = 5，P < 0.001）。EPO凝胶也诱导了类似的内膜过度增生。对用EPO溶液处理的动物的受损动脉进行免疫组织化学分析，结果显示外膜和中膜有显著的血管生成反应，从而解释了内膜过度增生的形成。尽管结果与预期相反，但它们解释了接受EPO治疗贫血的患者血液透析通路瘘管中出现更高程度狭窄的原因。这些结果也警示了EPO的使用，特别是对于有血管损伤风险或患有动脉粥样硬化疾病的患者。
