ADAMTS13-mediated angiogenesis by PLK-1/Ang-2 is independent of VEGF in diabetic retinopathy.

PURPOSE: A disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) has been found to increase and to be associated with diabetic retinopathy (DR). The study aimed to identify the role of ADAMTS13 in the pathogenesis of angiogenesis in DR.

METHODS: ADAMTS13 expression was evaluated in human retinal microvascular endothelial cells (HRMVECs), vitreous sample from patients with proliferative DR and diabetic mice model using Western blot, real time-quantitative PCR, immunofluorescence and ELISA. The effects of ADAMTS13 knockdown were studied in HRMVECs employing cell viability, tube formation, Transwell migration and wound healing assays and in diabetic mice using retinal trypsin digestion and Evans blue dye leakage assays. RNA-seq was applied to study the molecular mechanism of ADAMTS13 knockdown-mediated decreased neovascularization.

RESULTS: This study revealed that, among patients, high-glucose upregulated vitreous ADAMTS13 levels; in vitro, high-glucose concentration upregulated ADAMTS13, accompanied by increased cell proliferation, migration, and tube formation. ADAMTS13 knockdown decreased these changes. In vivo, in diabetic mice, retinal vascular leakage and acellular capillaries increased, and inhibition of ADAMTS13 reduced these changes. Furthermore, this study demonstrated that ADAMTS13 regulated the polo-like kinase-1 (PLK-1)/angiopoietin-2 (Ang-2) axis independent of vascular endothelial growth factor (VEGF) in DR.

CONCLUSION: Our study revealed the involvement of ADAMTS13 in DR development, as well as in angiogenesis through the PLK-1/Ang-2 signaling pathway. Targeting ADAMTS13-related pathways involved could serve as a novel therapeutic approach for patients with DR.