Newly Identified Peptide, Peptide Lv, Promotes Pathological Angiogenesis

BACKGROUND: We recently discovered a small endogenous peptide, peptide Lv, with the ability to activate vascular endothelial growth factor receptor 2 and its downstream signaling. As vascular endothelial growth factor through vascular endothelial growth factor receptor 2 contributes to normal development, vasodilation, angiogenesis, and pathogenesis of various diseases, we investigated the role of peptide Lv in vasodilation and developmental and pathological angiogenesis in this study. METHODS AND RESULTS: The endothelial cell proliferation, migration, and 3‐dimensional sprouting assays were used to test the abilities of peptide Lv in angiogenesis in vitro. The chick chorioallantoic membranes and early postnatal mice were used to examine its impact on developmental angiogenesis. The oxygen‐induced retinopathy and laser‐induced choroidal neovascularization mouse models were used for in vivo pathological angiogenesis. The isolated porcine retinal and coronary arterioles were used for vasodilation assays. Peptide Lv elicited angiogenesis in vitro and in vivo. Peptide Lv and vascular endothelial growth factor acted synergistically in promoting endothelial cell proliferation. Peptide Lv–elicited vasodilation was not completely dependent on nitric oxide, indicating that peptide Lv had vascular endothelial growth factor receptor 2/nitric oxide–independent targets. An antibody against peptide Lv, anti‐Lv, dampened vascular endothelial growth factor–elicited endothelial proliferation and laser‐induced vascular leakage and choroidal neovascularization. While the pathological angiogenesis in mouse eyes with oxygen‐induced retinopathy was enhanced by exogenous peptide Lv, anti‐Lv dampened this process. Furthermore, deletion of peptide Lv in mice significantly decreased pathological neovascularization compared with their wild‐type littermates. CONCLUSIONS: These results demonstrate that peptide Lv plays a significant role in pathological angiogenesis but may be less critical during development. Peptide Lv is involved in pathological angiogenesis through vascular endothelial growth factor receptor 2–dependent and –independent pathways. As anti‐Lv dampened the pathological angiogenesis in the eye, anti‐Lv may have a therapeutic potential to treat pathological angiogenesis.