Apolipoprotein E knockout attenuates vascular graft fibrosis by reducing 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. It can also lead to 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 Apolipoprotein E (APOE) significantly increased during vascular regeneration after graft implantation in vivo. APOE knockout (KO) increased compliance of the regenerated aortas, reduced extracellular matrix (ECM) deposition, and increased capillary ingrowth 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. APOE KO reduced the formation of profibrotic macrophages during vascular regeneration. The interaction between APOE and low-density lipoprotein receptor related protein 1 (LRP1) partially mediated the profibrotic macrophage formation. The profibrotic macrophages promoted graft fibrosis mainly through secretion of insulin-like growth factor-1 (IGF-1) that could support fibroblast proliferation. Finally, we showed that APOE knockdown in vivo using adeno-associated virus (AAV) improved the compliance of the regenerated aortas, reduced extracellular matrix (ECM) deposition and increased capillary ingrowth in the adventitial areas of the regenerated aortas by reducing the formation of profibrotic macrophages and their secreted IGF-1. Collectively, these data indicate that APOE can promote profibrotic macrophage formation partially through LRP1, and the profibrotic macrophages mediate graft fibrosis by increasing fibroblast proliferation via IGF-1. Inhibition of APOE generation in regenerated aortas can alleviate graft fibrosis that occurs during vascular regeneration.