经载有阿司匹林触发型 resolvin D1 的血管移植物修饰调控炎症反应,促进血管再生。
Regulation of the inflammatory response by vascular grafts modified with Aspirin-Triggered Resolvin D1 promotes blood vessel regeneration.
机构信息
Key Laboratory of Bioactive Materials for Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.
Key Laboratory of Bioactive Materials for Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.
出版信息
Acta Biomater. 2019 Oct 1;97:360-373. doi: 10.1016/j.actbio.2019.07.037. Epub 2019 Jul 24.
The unabated inflammatory response is often the cause for inhibited vascular regeneration of transplanted small-diameter vascular grafts (diameter <6 mm) in vascular replacement therapies. We proposed that stimulating inflammatory resolution could be an effective approach for treatment of chronic vascular graft inflammation after transplantation. Aspirin-Triggered Resolvin D1 (AT-RvD1) plays critical roles in driving cellular processes toward the resolution of inflammation and suppressing downstream inflammatory signaling pathways. With the aim to facilitate vascular regeneration, we developed a polycaprolactone (PCL) vascular graft loaded with AT-RvD1. The results showed that AT-RvD1 promoted macrophage polarization into M2 macrophages in vitro. Macrophages pretreated with AT-RvD1 conditioned medium promoted endothelial cell tube formation. Furthermore, in vivo implantation was performed by replacing rat abdominal aorta. We observed fast endothelialization and enhanced smooth muscle regeneration in rats that received the AT-RvD1-containing graft implants. The presence of AT-RvD1 induced infiltration of a large number of M2 macrophages and integrin α4-positive (CD49d) neutrophils into the graft wall after implantation. Vascular graft RNA-Seq analysis revealed that AT-RvD1 inhibited leukocyte and neutrophil migration and activation. Results also indicated that macrophage polarization to the M2 phenotype was promoted on day 7 post-implantation. These results demonstrated the ability of locally delivered AT-RvD1 to increase pro-regenerative immune subpopulations and promote vascular tissue regeneration. STATEMENT OF SIGNIFICANCE: Chronic inflammation is a key deciding factor in the failure of vascular regeneration of transplanted small-diameter vascular grafts (diameter <6 mm). Aspirin-triggered Resolvin D1 (AT-RvD1) is a critical driving force in cellular resolution inflammation and suppresses inflammatory signaling. Herein, we developed an electrospun polycaprolactone (PCL) vascular graft loaded with AT-RvD1. In vivo implantation was performed by replacing rat abdominal aorta and AT-RvD1-loaded grafts showed rapid endothelialization, enhanced capillary formation, and excellent smooth muscle regeneration by regulating inflammatory reaction and promoting its rapid resolution. Thus, our study provided new perspectives for long-term vascular graft survival and integration with the host tissue. We believe that AT-RvD1 can be widely applied in tissue engineering owing to its anti-inflammatory and therapeutic effects.
未受抑制的炎症反应通常是血管替代治疗中小直径血管移植物(直径<6mm)血管再生受到抑制的原因。我们提出,刺激炎症消退可能是治疗移植后慢性血管移植物炎症的有效方法。阿司匹林触发的分辨率 D1(AT-RvD1)在驱动细胞过程向炎症消退和抑制下游炎症信号通路方面发挥着关键作用。为了促进血管再生,我们开发了一种负载 AT-RvD1 的聚己内酯(PCL)血管移植物。结果表明,AT-RvD1 促进了体外巨噬细胞向 M2 巨噬细胞的极化。用 AT-RvD1 条件培养基预处理的巨噬细胞促进了内皮细胞管形成。此外,通过替换大鼠腹主动脉进行体内植入。我们观察到接受含 AT-RvD1 移植物植入的大鼠快速内皮化和增强的平滑肌再生。植入后,AT-RvD1 诱导大量 M2 巨噬细胞和整合素 α4 阳性(CD49d)中性粒细胞浸润移植物壁。血管移植物 RNA-Seq 分析显示,AT-RvD1 抑制白细胞和中性粒细胞迁移和激活。结果还表明,植入后第 7 天,巨噬细胞向 M2 表型的极化得到促进。这些结果表明局部递送 AT-RvD1 能够增加促再生免疫亚群并促进血管组织再生。
意义声明
慢性炎症是移植小直径血管移植物(直径<6mm)血管再生失败的关键决定因素。阿司匹林触发的分辨率 D1(AT-RvD1)是细胞分辨率炎症的关键驱动力,可抑制炎症信号。在此,我们开发了一种负载 AT-RvD1 的静电纺聚己内酯(PCL)血管移植物。通过替换大鼠腹主动脉进行体内植入,负载 AT-RvD1 的移植物表现出快速内皮化、增强的毛细血管形成和出色的平滑肌再生,通过调节炎症反应和促进其快速消退。因此,我们的研究为长期血管移植物的存活和与宿主组织的整合提供了新的视角。我们相信,由于其抗炎和治疗作用,AT-RvD1 可以在组织工程中得到广泛应用。