Identification of a novel anti-angiogenic regulatory sequence within the syndecan-3 extracellular core protein

Syndecans are transmembrane proteoglycans that regulate angiogenesis through their glycosaminoglycan chains and core proteins. We previously demonstrated that the syndecan-3 (SDC3) extracellular core protein possesses anti-angiogenic activity independent of its glycosaminoglycan chains. Here, using recombinant truncation mutants, endothelial migration assays and peptide mapping, we localised this activity and identified a minimal nine amino acid peptide, QM111, that retained full biological activity. QM111 inhibited endothelial cell migration and angiogenic sprouting in rat aortic ring and mouse choroidal explant models. Intrinsic disorder analysis revealed that QM111 resides within a region of comparatively reduced disorder, consistent with other syndecan regulatory sequences. QM111 did not induce inflammatory chemokine production, exhibited no detectable cytotoxicity, and retained substantial stability in human serum and vitreous humour. QM111 displayed anti-angiogenic activity comparable to the previously described syndecan-2-derived peptide QM107, with combination treatment producing robust inhibition of angiogenesis. These findings identify a novel anti-angiogenic regulatory sequence within SDC3 and support the concept that syndecan extracellular core proteins contain biologically active sequences with potential therapeutic utility.