Prunetin-Functionalized Small-Diameter Vascular Grafts Attenuate Restenosis through Endothelial Regeneration

Tissue-engineered vascular grafts (TEVGs), particularly small-diameter vascular grafts (SDVGs), continue to face significant clinical challenges such as delayed endothelialization, acute thrombosis, and intimal hyperplasia, which severely compromise long-term patency. Consequently, developing SDVGs with superior antithrombotic properties and efficient endothelial regenerative capacity is of strategic importance for the advancement of cardiovascular therapies. Through the connectivity map (CMap) algorithm screening, prunetin (Pru), a natural flavonoid, was identified as a promising candidate. This study represents the first report of the incorporation of Pru into a functionalized vascular graft. Our findings demonstrate that Pru effectively promotes the proliferation, migration, and maturation of vascular endothelial cells, thereby accelerating graft endothelialization. Moreover, Pru-loaded grafts significantly inhibit calcification and enhance extracellular matrix remodeling, contributing to the improved patency. Transcriptomic and network pharmacology analyses revealed that Pru primarily exerts its effects by inhibiting the NF-κB inflammatory pathway and activating the Nrf2/HO-1 antioxidant signaling axis. This synergistic multipathway regulation restores endothelial function, mitigates cellular dysfunction, and facilitates vascular regeneration. This work establishes a theoretical framework and translational strategy for cardiovascular treatment, demonstrating the potential of Pru as a potent pro-endothelialization agent and providing a strategic direction for the advancement of functionalized SDVGs.