Pharmacological manipulation of macrophage autophagy effectively rejuvenates the regenerative potential of biodegrading vascular graft in aging body.

Abstract

Declined regenerative potential and aggravated inflammation upon aging create an inappropriate environment for arterial regeneration. Macrophages are one of vital effector cells in the immune microenvironment, especially during biomaterials mediated repairing process. Here, we revealed that the macrophage autophagy decreased with aging, which led to aggravated inflammation, thereby causing poor vascular remodeling of artificial grafts in aging body. Through loading the autophagy-targeted drugs, rapamycin and 3-MA (3-methyladenine), in PCL (polycaprolactone) sheath of the PGS (poly glycerol sebacate) - PCL vascular graft, the essential role of macrophage autophagy was confirmed in regulating macrophage polarization and biomaterial degradation. Moreover, the utilization of rapamycin promoted anti-inflammatory polarization of macrophage by activating autophagy, which further promoted myogenic differentiation of vascular progenitor cells and accelerated endothelialization. Our study elucidated the contribution of pharmacological manipulation of macrophage autophagy in promoting regeneration of small caliber artery, which may pave a new avenue for clinical translation of vascular grafts in aging body.