α‑Ketoglutaric\nAcid Reprograms Macrophages\nby Altering Energy Metabolism to Promote the Regeneration of Small-Diameter\nVascular Grafts

Small-diameter vascular grafts still cannot clinically\nreplace\nautologous blood vessels due to high restenosis rates caused by long-term\ninflammatory infiltration. Foreign body reactions to vascular grafts\ninduce macrophages to adopt the pro-inflammatory M1 phenotype, releasing\ninflammatory factors such as interleukin-1β (IL-1β) and\ntumor necrosis factor-α (TNF-α). This induces a phenotypic\nswitch in smooth muscle cells, eventually leading to intimal hyperplasia.\nHerein, we constructed small-diameter artificial vascular grafts capable\nof modulating immune responses through the controlled release of α-ketoglutaric\nacid (α-KG). Our findings verify that the delivery of α-KG\nreprograms the macrophage phenotype from a pro-inflammatory M1 to\nan anti-inflammatory and pro-repair M2 phenotype by regulating the\nenergy metabolism of the tricarboxylic acid cycle (TAC). More interestingly,\nthe delivery of α-KG positively influences the behavior of vascular\ncells by enhancing the proliferation of human umbilical vein endothelial\ncells (HUVECs) and inhibiting the expansion of mouse aortic vascular\nsmooth muscle cells (MOVAS), thereby reducing vascular restenosis.\nIn vivo evaluation in rabbit carotid artery replacement confirms the\noptimal performance of α-KG-doped vascular grafts in terms of\nendothelial coverage and long-term patency. Collectively, our work\npresents a promising approach for creating artificial vascular grafts\nwith inflammatory regulation to ensure rapid endothelialization and\nsustained patency.