Improving Vascular Regeneration Performance of Electrospun Poly(epsilon-Caprolactone) Vascular Grafts via Synergistic Functionalization with VE-Cadherin/VEGF

In vivo, vascular endothelial growth factor (VEGF) and vascular endothelial cadherin (VE-cadherin) co-regulate the dynamic organization of endothelial cells during vascular sprouting, balancing angiogenesis and vascular stability. In this study, a novel bioactive surface integrating human VE-cadherin-Fc and VEGF-Fc fusion proteins was innovatively developed for the modification of poly(epsilon-caprolactone) (PCL) small-caliber electrospun fibrous grafts (VE-cad/VEGF-PCL) to promote the regeneration of functional endothelium and improve the patency of artificial vascular grafts. These fusion proteins self-assembled on the PCL fibers through the hydrophobic binding of Fc domains, improving surface hydrophilicity while reducing the adhesion of fibrinogen. In vitro results showed that the VE-cadherin/VEGF surface upregulated the expression of endogenous VE-cadherin and synergistically activated the VE-cadherin/VEGFR2/FAK/AKT/ERK signal transduction, which facilitated the functioning of human umbilical vein endothelial cells (HUVECs). Moreover, the VE-cadherin/VEGF surface significantly enhanced cellularization and capillary formation, then subsequently accelerated the regeneration of functional endothelium and smooth muscle in the VE-cad/VEGF-PCL grafts in a rat abdominal aorta replacement model. Together, these results highlight the advantages of VE-cadherin/VEGF surface in enhancing rapid endothelialization of electrospun vascular grafts and provide new insights into the design of cross-activating biomaterials.