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Study on the Role of Short Peptide LCKLSL Targeting ANXA2 in Retinal Neovascularization
Jiale Bai1,2, Yini Wang1,2, Shihong Zhao3,2,4
1Aier Academy of Ophthalmology, Central South University, Hunan, P.R. China.
Background/Aim:
Annexin A2 (ANXA2), functioning as a co-receptor for tissue plasminogen activator (tPA) and plasminogen, plays a critical role in retinal neovascularization (RNV). The hexapeptide LCKLSL competitively inhibits ANXA2 activity, offering a potential therapeutic strategy for RNV in retinopathy of prematurity (ROP). This study investigated the efficacy and biosafety of LCKLSL in suppressing RNV using an oxygen-induced retinopathy (OIR) model in C57BL/6J mice.
Materials And Methods:
LCKLSL was administered via intravitreal injection, with RNV inhibition evaluated through retinal immunofluorescence and hematoxylin-eosin (HE) staining. Comprehensive safety assessments encompassing short- and long-term evaluations were performed using retinal thickness measurements, electroretinography (ERG), and histological analyses of hepatic/renal tissues. Immunohistochemistry confirmed ANXA2-RNV colocalization and LCKLSL targeting specificity. Molecular mechanisms were analyzed using enzyme-linked immunosorbent assay (ELISA) to quantify cell-surface tPA binding in human retinal microvascular endothelial cells (HRMECs), while qRT-PCR and western blot were employed to detect RNV-related factors. Complementary in vitro experiments using hypoxia-induced human umbilical vein endothelial cells (HUVECs) assessed cellular safety (CCK-8 and TUNEL assays) and therapeutic effects on migration (Wound healing assay), angiogenesis (Matrigel tube formation), and invasion (Transwell assay).
Results:
LCKLSL significantly attenuated RNV formation without inducing pathological alterations in retinal structure or systemic toxicity. Mechanistically, LCKLSL reduced cell-surface tPA binding and suppressed vascular endothelial growth factor (VEGF) and metalloproteinase (MMP) expression at mRNA and protein levels. In vitro, LCKLSL inhibited HUVEC migration, tube formation, and invasion under hypoxia.
Conclusion:
LCKLSL acts as a potent ANXA2-targeted inhibitor of pathological angiogenesis and demonstrates a favorable biosafety profile, highlighting its promising therapeutic potential for the treatment of RNV-related disorder.
