Netrin‐1 Promotes Inflammation Resolution to Achieve Endothelialization of Small‐Diameter Tissue Engineering Blood Vessels by Improving Endothelial Progenitor Cells Function In Situ

Abstract

The transplant of small‐diameter tissue engineering blood vessels (small‐diameter TEBVs) (<6 mm) in vascular replacement therapy often fails because of early onset thrombosis and long‐standing chronic inflammation. The specific inflammation state involved in small‐diameter TEBVs transplants remains unclear, and whether promoting inflammation resolution would be useful for small‐diameter TEBVs therapy need study. The neural protuberant orientation factor 1 (Netrin‐1) is found present in endothelial cells of natural blood vessels and has anti‐inflammatory effects. This work generates netrin‐1‐modified small‐diameter TEBVs by using layer‐by‐layer self‐assembly to resolve the inflammation. The results show that netrin‐1 reprograms macrophages (MΦ) to assume an anti‐inflammatory phenotype and promotes the infiltration and subsequent efflux of MΦ from inflamed sites over time, which improves the local microenvironment and the function of early homing endothelial progenitor cells (EPCs). Small‐diameter TEBVs modified by netrin‐1 achieve endothelialization after 30 d and retain patency at 14 months. These findings suggest that promoting the resolution of inflammation in time is necessary to induce endothelialization of small‐diameter TEBVs and prevent early thrombosis and problems associated with chronic inflammation. Furthermore, this work finds that the MΦ‐derived exosomes can target and regulate EPCs, which may serve as a useful treatment for other inflammatory diseases.

Netrin‐1 and its receptor Unc5b as markers of periodontal disease

“…Studies have revealed that monocytes/macrophages are the key components of the host response and the accumulation of those cells into the periodontal tissues cause the prolonged chronic inflammation . In addition to the regulation of immune cell migration, Netrin‐1 was shown to regulate the inflammatory response of macrophages through suppression of COX‐2–mediated PGE2 production and also promote macrophage reprogramming to induce inflammation resolution . Furthermore, Netrin‐1 binding with its receptor Unc5b takes part in osteoclast biology and thus suggested as a therapeutic target for inflammatory bone destructive diseases .…”

“…24 In addition to the regulation of immune cell migration, Netrin-1 was shown to regulate the inflammatory response of macrophages through suppression of COX-2-mediated PGE2 production 9 and also promote macrophage reprogramming to induce inflammation resolution. 8,25,26 Furthermore, Netrin-1 binding with its receptor Unc5b takes part in osteoclast biology 14 and thus suggested as a therapeutic target for inflammatory bone destructive diseases. 13,27 In this study, Netrin-1 and its receptor Unc5b were detected in all samples.…”

“…It has been reported that Netrin‐1 regulates the inflammatory response through suppression of COX‐2–mediated PGE2 production and HIF‐1alpha‐dependent induction of Netrin‐1 has been demonstrated to attenuate hypoxia‐elicited inflammation at mucosal surfaces . One mechanism of the anti‐inflammatory effect of Netrin‐1 is induction of M2 macrophage polarization through PPAR pathways and therefore promotes inflammation resolution …”

“…11 One mechanism of the anti-inflammatory effect of Netrin-1 is induction of M2 macrophage polarization through PPAR pathways and therefore promotes inflammation resolution. 8 Tadagavadi, et al 12…”

“…4 Recent studies have demonstrated that the expression of Netrin-1 is not limited with the nervous system. This molecule functions in both acute and chronic inflammatory diseases via controlling angiogenesis, 5,6 regulation of immune cell recruitment, 7 macrophage reprogramming, 8 and regulation of cyclooxygenase-2 pathways. 9 Netrin-1, acting via its receptor UNC5b, is shown to be a potent inhibitor of monocyte and lymphocyte migration in vitro and in vivo.…”