Proangiogenic Collagen Binding Glycan Therapeutic Promotes Endothelial Cell Health: Potential Application for the Treatment of Ischemic Wounds

Abstract

Peripheral artery disease and endothelial cell dysfunction due to diabetes contribute to impaired neovascularization and poor healing of ischemic wounds. Treatments addressing this underlying ischemia that remain effective in the highly proteolytic diabetic wound environment are urgently needed to increase the rate of wound healing and reduce diabetes-related lower-limb amputations. Our lab has previously designed a collagen-targeted glycan therapeutic (DS-SILY) capable of protecting collagen-based scaffolds from matrix metalloproteinase (MMP) mediated degradation. Building upon this targeted technology, we designed the next generation glycan therapy, termed LXW7-DS-SILY (LDS), to also contain proangiogenic capabilities. By exploiting αvβ3 integrin-mediated VEGF signaling using our previously identified αvβ3 integrin targeted peptide (LXW7), we propose an alternative strategy to overcome shortcomings of traditional growth factor therapy. In this study, we describe the synthesis and optimization of LDS variants and evaluate their angiogenic potential in vitro and in vivo. LDS displayed binding to collagen and endothelial cells. In vitro, the LDS variant with 6 LXW7 peptides increased endothelial cell proliferation, migration, and tubule formation through increased VEGFR2 phosphorylation compared to non-treated controls. In vivo in a chick chorioallantoic membrane (CAM) assay, LDS laden collagen hydrogels increased blood vessel formation by 43% in comparison to organism matched blank hydrogels. Overall, these findings demonstrate the potential of a robust proangiogenic targeted therapeutic for the treatment of ischemic diabetic wounds.