Regulation of the inflammatory response by vascular grafts modified with Aspirin-Triggered Resolvin D1 promotes blood vessel regeneration

Abstract

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 SignificanceChronic 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.