Vasculoprotective effects of erythropoietin: new developments and new alternatives.
Vasculoprotective effects of erythropoietin: new developments and new alternatives.
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促红细胞生成素的血管保护作用：新进展和新替代品。
DOI：
10.1161/01.res.0000228463.96905.45
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发表时间：
2006
影响因子：
20.1
通讯作者：
Simari,RobertD
中科院分区：
文献类型：
--
作者：
Kiernan,ThomasJ;Simari,RobertD
证明基于细胞的直接疗法抑制血管损伤的急性反应的血管保护作用的证据继续增加。将具有内皮表型的自体循环来源的细胞输送到受损的动脉段，可导致血管功能的早期再内皮化和正常化。1-3目前这种方法的应用需要在体外进行细胞分离和修饰，然后直接输送。然而，正在开发新的方法来避免这一战略固有的翻译问题。总的来说，这些新的方法包括动员和靶向能够增强受损动脉内皮化的细胞群，同时限制新的内膜形成。多种细胞因子已经被证明能够动员能够呈现内皮表型(广泛地称为内皮祖细胞)的细胞。这些细胞因子包括血管内皮生长因子、粒细胞集落刺激因子、粒细胞集落刺激因子和促红细胞生成素。Urao等人在本期《循环研究》上发表的文章扩展了以下观察结果：EPO可以动员内皮祖细胞，同时展示了其以非依赖性方式促进血管损伤后再内皮化和抑制新生内膜形成的能力。综上所述，这些发现扩大了我们对EPO作为组织保护剂的作用的理解，并将其应用于急性血管损伤的设定。Urao的文章在小鼠颈动脉钢丝损伤模型中测试了系统注射重组人EPO将抑制新生内膜形成的假设。4动脉损伤后给予EPO(1000IU/kg体重)，连续3d。损伤后14天进行的连续动脉切片的形态计量分析显示，与生理盐水注射组相比，EPO处理组小鼠的新生内膜面积减少了52%。在一系列精心设计的实验中，他们进一步证明了EPO介导的对新生内膜形成的抑制是eNOS/NO依赖的。用一氧化氮供体L精氨酸、eNOS抑制剂L-NAME治疗野生型小鼠，并在eNOS阴性小鼠中进行动脉损伤。从死前给药的动脉组织伊文斯蓝染色的动脉组织染色可以证明，EPO治疗的动物比未治疗组的再内皮化程度更大。CD31免疫组织化学染色显示，EPO介导的再内皮化区有55%来自骨髓来源的细胞。尽管促红细胞生成素使血红蛋白值增加，但与未治疗的动物相比，促红细胞生成素治疗的动物的血栓形成并没有增加。促红细胞生成素是如何减少新生内膜形成和促进再内皮化的？Urao和他的同事在动脉损伤后3天收集了EPO和生理盐水处理的动物的外周血液。流式细胞仪分析显示，CD45dim/Flk-1+标记显示EPO处理组的EPC数量高于生理盐水组。为了鉴定这些细胞为内皮细胞系，进一步在体外培养了7天。大多数CD45dim/Flk-1+细胞与FITC结合的BS-1凝集素结合，并结合Dil标记的acLDL。同样，EpoE处理的小鼠的内皮样细胞的相对数量比生理盐水注射对照组的小鼠更多。值得注意的是，EPO受体(EPOR)的表达定位于新生血管内皮细胞，尤其是CD31+的内皮细胞。
The body of evidence demonstrating the vasculoprotec-tive effects of direct cell-based therapies to inhibit the acute response to vascular injury continues to grow. Delivery of autologous circulation-derived cells capable of assuming an endothelial phenotype to an injured arterial segment results in early reendothelialization and normalization of vascular function. 1–3 Current applications of this approach require cell isolation and modification in vitro, followed by direct delivery. However, novel approaches are being developed to avoid the inherent translational concerns of this strategy. Broadly, these new approaches include the mobilization and targeting of cell populations capable of augmenting reendothelialization of injured arteries while limiting neointimal formation. Multiple cytokines have been shown to mobilize cells capable of assuming an endothelial phenotype (broadly known as EPCs). These cytokines include VEGF, G-CSF, GM-CSF, and erythropoietin (Epo). The article by Urao et al4 in this issue of Circulation Research extends the observation that Epo can mobilize EPCs while demonstrating its ability to enhance reendothelialization and inhibit neointimal formation after vascular injury in an NO-dependent manner. Taken together, these findings extend our understanding of the role of Epo as a tissue protectant and apply it to the setting of acute vascular injury. The article by Urao tested the hypothesis that systemic delivery of recombinant human Epo would inhibit neointimal formation in a mouse carotid artery wire injury model. 4 Epo (1000 IU/kg of body weight) was administered for 3 days beginning at the time of arterial injury. Morphometric analysis of serial arterial sections performed at 14 days after injury showed a 52% decrease in the neointimal area in the Epo-treated mice compared with the saline injected group. They further demonstrated that Epo-mediated inhibition of the neointimal formation is eNOS/NO-dependent in a series of well constructed experiments treating wild-type mice with the nitric oxide donor, L-Arginine, the eNOS inhibitor, L-NAME, and performing arterial injury in eNOS-null mice.Reendothelialization was greater in the Epo-treated animals than in the nontreated group as evidenced by staining of arterial tissue with Evans blue dye which was administered premortem. Immunostaining with antibodies to CD31 indicated that 55% of Epo-mediated reendothelialized area was derived from marrow-derived cells. Even though hemoglobin values were increased in response to Epo, there was no increase in thrombosis formation in Epo-treated animals compared with nontreated animals. How does Epo produce a decrease in neointima formation and enhance reendothelialization? Urao and colleagues collected peripheral blood from Epo-and saline-treated animals 3 days after arterial injury. FACS analysis revealed a higher quantity of EPCs as determined by CD45dim/Flk-1+ labeling in the Epo-treated group as opposed to the saline-treated group. To identify these cells as those of endothelial lineage, they were further cultured for 7 days in vitro. The majority of these CD45dim/FLK-1+ cells bound FITC-conjugated BS-1 lectin and incorporated Dil-labeled acLDL. Again the relative numbers of endothelial like cells were greater in the Epotreated mice than in the saline-injected controls. Of particular note, Epo receptor (EpoR) expression was localized on the regenerated endothelium especially on the CD31+ endothelial cells in Epo-treated arteries compared with saline injected arteries.