BACKGROUND:Transplant arteriosclerosis is a major complication in long-term survivors of heart transplantation. Increased lymph flow from donor heart to host lymph nodes has been reported to play a role in transplant arteriosclerosis, but how lymphangiogenesis affects this process is unknown.METHODS:Vascular allografts were transplanted among various combinations of mice, including wild-type, Lyve1-CreER^T2;R26-tdTomato, CAG-Cre-tdTomato, severe combined immune deficiency, Ccr2^KO, Foxn1^KO, and lghm/lghd^KO mice. Whole-mount staining and 3-dimensional reconstruction identified lymphatic vessels within the grafted arteries. Lineage tracing strategies delineated the cellular origin of lymphatic endothelial cells. Adeno-associated viral vectors and a selective inhibitor were used to regulate lymphangiogenesis.RESULTS:Lymphangiogenesis within allograft vessels began at the anastomotic sites and extended from preexisting lymphatic vessels in the host. Tertiary lymphatic organs were identified in transplanted arteries at the anastomotic site and lymphatic vessels expressing CCL21 (chemokine [C-C motif] ligand 21) were associated with these immune structures. Fibroblasts in the vascular allografts released VEGF-C (vascular endothelial growth factor C), which stimulated lymphangiogenesis into the grafts. Inhibition of VEGF-C signaling inhibited lymphangiogenesis, neointima formation, and adventitial fibrosis of vascular allografts. These studies identified VEGF-C released from fibroblasts as a signal stimulating lymphangiogenesis extending from the host into the vascular allografts.CONCLUSIONS:Formation of lymphatic vessels plays a key role in the immune response to vascular transplantation. The inhibition of lymphangiogenesis may be a novel approach to prevent transplant arteriosclerosis.

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淋巴管生成在移植动脉硬化中的作用

背景：移植动脉硬化是心脏移植长期幸存者的主要并发症。据报道，从供体心脏到宿主淋巴结的淋巴流量增加在移植动脉硬化中发挥作用，但淋巴管生成如何影响这一过程尚不清楚。 方法：将血管同种异体移植物移植到各种组合的小鼠中，包括野生型、Lyve1 -CreER ^T2；R26-tdTomato、CAG-Cre-tdTomato、严重联合免疫缺陷、Ccr2 ^KO、Foxn1 ^KO和lghm / lghd ^KO小鼠。整体染色和三维重建鉴定了移植动脉内的淋巴管。谱系追踪策略描绘了淋巴管内皮细胞的细胞起源。腺相关病毒载体和选择性抑制剂被用来调节淋巴管生成。结果：同种异体移植血管内的淋巴管生成从吻合部位开始，并从宿主体内预先存在的淋巴管延伸。在吻合部位的移植动脉中鉴定出第三淋巴器官，表达 CCL21（趋化因子 [CC 基序] 配体 21）的淋巴管与这些免疫结构相关。同种异体血管移植物中的成纤维细胞释放 VEGF-C（血管内皮生长因子 C），刺激移植物中的淋巴管生成。抑制 VEGF-C 信号传导可抑制同种异体血管移植物的淋巴管生成、新内膜形成和外膜纤维化。这些研究确定成纤维细胞释放的 VEGF-C 是刺激淋巴管生成的信号，从宿主延伸到血管同种异体移植物。结论：淋巴管的形成在血管移植的免疫反应中起着关键作用。抑制淋巴管生成可能是预防移植动脉硬化的新方法。