Sustained, indolent immune injury of the vasculature of a heart transplant limits long-term graft and recipient survival. This injury is mitigated by a poorly characterized, maladaptive repair response. Vascular endothelial cells respond to proangiogenic cues in the embryo by differentiation to specialized phenotypes, associated with expression of apelin. In the adult, the role of developmental proangiogenic cues in repair of the established vasculature is largely unknown. We found that human and minor histocompatibility–mismatched donor mouse heart allografts with alloimmune-mediated vasculopathy upregulated expression of apelin in arteries and myocardial microvessels. In vivo, loss of donor heart expression of apelin facilitated graft immune cell infiltration, blunted vascular repair, and worsened occlusive vasculopathy in mice. In vitro, an apelin receptor agonist analog elicited endothelial nitric oxide synthase activation to promote endothelial monolayer wound repair and reduce immune cell adhesion. Thus, apelin acted as an autocrine growth cue to sustain vascular repair and mitigate the effects of immune injury. Treatment with an apelin receptor agonist after vasculopathy was established markedly reduced progression of arterial occlusion in mice. Together, these initial data identify proangiogenic apelin as a key mediator of coronary vascular repair and a pharmacotherapeutic target for immune-mediated injury of the coronary vasculature.

中文翻译：

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免疫介导的损伤后，Apelin指导内皮细胞分化和血管修复

心脏移植血管的持续，惰性免疫损伤限制了长期移植物和受体的存活。特征不佳的适应不良的修复反应可减轻这种伤害。血管内皮细胞通过分化成与apelin表达有关的特殊表型来响应胚胎中的促血管生成信号。在成年人中，发育性血管生成线索在修复已建立的脉管系统中的作用在很大程度上是未知的。我们发现，人类和次要组织相容性不匹配的供体小鼠心脏同种异体移植与同种免疫介导的血管病变可上调动脉和心肌微血管中apelin的表达。在体内，apelin供体心脏表达的丧失促进小鼠的移植免疫细胞浸润，钝化的血管修复和更严重的闭塞性血管病。体外，apelin受体激动剂类似物引起内皮一氧化氮合酶激活，从而促进内皮单层伤口修复并减少免疫细胞粘附。因此，apelin充当自分泌生长的线索，以维持血管修复并减轻免疫损伤的影响。确定血管病变后用apelin受体激动剂进行治疗可明显降低小鼠动脉闭塞的进展。总之，这些初步数据确定促血管生成的apelin是冠状动脉修复的关键介质，也是免疫介导的冠状血管损伤的药物治疗靶标。apelin充当自分泌生长的线索，以维持血管修复并减轻免疫损伤的影响。确定血管病变后用apelin受体激动剂进行治疗可明显降低小鼠动脉闭塞的进展。总之，这些初步数据确定促血管生成的apelin是冠状动脉修复的关键介质，也是免疫介导的冠状血管损伤的药物治疗靶标。apelin充当自分泌生长的线索，以维持血管修复并减轻免疫损伤的影响。确定血管病变后用apelin受体激动剂治疗可明显降低小鼠动脉闭塞的进展。总之，这些原始数据确定促血管生成的apelin是冠状动脉修复的关键介质，也是免疫介导的冠状血管损伤的药物治疗靶标。