APOE knockout attenuates vascular graft fibrosis by limiting profibrotic macrophage formation through low-density lipoprotein receptor related protein 1

Vascular graft fibrosis can cause a decrease in cellular infiltration and capillary ingrowth in vascular walls and vascular stiffening. As such, there are still no vascular grafts that can be used in blood vessels where their diameters are less than 6 mm in patients. Although various approaches have been evaluated to mitigate implant-associated fibrosis, effective treatments remain quite limited. In this study, we demonstrated that APOE was significantly increased during vascular regeneration after graft implantation in vivo. APOE knockout (KO) increased compliance of regenerated aortas and reduced extracellular matrix (ECM) deposition in adventitia of the regenerated aortas. Using single cell RNA sequencing (scRNA-seq), a subset of profibrotic macrophages was found to be involved in graft fibrosis and APOE KO limited the formation of profibrotic macrophage formation during vascular regeneration. The interaction between APOE and low-density lipoprotein receptor related protein 1 (LRP1) partially mediated fibrotic differentiation of the macrophages. Profibrotic macrophages promoted graft fibrosis mainly through secretion of insulin-like growth factor-1 (IGF-1) that could support proliferation of fibroblasts. Finally, we showed that APOE knockdown in vivo using adeno-associated virus (AAV) improved the compliance of regenerated aortas and reduced ECM deposited in the adventitial areas by limiting formation of profibrotic macrophages. Collectively, these data indicate that APOE promotes the profibrotic transition of macrophages partially through LRP1, and the profibrotic macrophages increase the proliferation of fibroblasts via IGF-1. Inhibition of APOE by AAV can alleviate graft fibrosis occurring during vascular regeneration.