α-Ketoglutaric Acid Reprograms Macrophages by Altering Energy Metabolism to Promote the Regeneration of Small-Diameter Vascular Grafts.

Small-diameter vascular grafts still cannot clinically replace autologous blood vessels due to high restenosis rates caused by long-term inflammatory infiltration. Foreign body reactions to vascular grafts induce macrophages to adopt the pro-inflammatory M1 phenotype, releasing inflammatory factors such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). This induces a phenotypic switch in smooth muscle cells, eventually leading to intimal hyperplasia. Herein, we constructed small-diameter artificial vascular grafts capable of modulating immune responses through the controlled release of α-ketoglutaric acid (α-KG). Our findings verify that the delivery of α-KG reprograms the macrophage phenotype from a pro-inflammatory M1 to an anti-inflammatory and pro-repair M2 phenotype by regulating the energy metabolism of the tricarboxylic acid cycle (TAC). More interestingly, the delivery of α-KG positively influences the behavior of vascular cells by enhancing the proliferation of human umbilical vein endothelial cells (HUVECs) and inhibiting the expansion of mouse aortic vascular smooth muscle cells (MOVAS), thereby reducing vascular restenosis. In vivo evaluation in rabbit carotid artery replacement confirms the optimal performance of α-KG-doped vascular grafts in terms of endothelial coverage and long-term patency. Collectively, our work presents a promising approach for creating artificial vascular grafts with inflammatory regulation to ensure rapid endothelialization and sustained patency.