Targeting STAT5 attenuates retinal neovascularization by promoting apoptosis and suppressing endothelial cell function.

Abstract

Signal transducer and activator of transcription 5 (STAT5) is well established as an essential regulator of tumor growth and angiogenesis. However, its specific role in retinal neovascularization (RNV) remains unclear. This research aims to elucidate the function of STAT5 in RNV progression and to identify the underlying molecular pathways. An oxygen-induced retinopathy (OIR) model was developed using C57BL/6 mice exposed to 75 ± 3 % Ofrom postnatal day 7 (P7) to P12 and injected intravitreally with a STAT5 inhibitor (10 μM) at P12. Western blot and immunofluorescence were used to evaluate protein expression at P15 and P18. Neovascularization was quantified using a whole retinal flat-mount, and apoptosis was detected using Tunnel assay at P18. Human retinal microvascular endothelial cells (HRMVECs) were cultured for 12 h under normoxic (21 % O) or hypoxic (1 % O) conditions to assess the effects of the STAT5 inhibitor (2 μM) on cell proliferation, migration, and tube formation. STAT5 and phosphorylated STAT5 (p-STAT5) levels were elevated in the retinas of OIR mice, which exhibited colocalization in neovascular regions. The areas with RNV were significantly reduced by treatment with a STAT5 inhibitor, which also decreased STAT5 and p-STAT5 levels. Inhibiting STAT5 in the OIR mice elevated the expression of apoptotic markers, including PARP-1, Caspase-3/9, and Bax/Bcl-2. The STAT5 inhibitor significantly promoted apoptosis in the retinal neovascular regions. Furthermore, the proliferation, migration, invasion, and tube-forming capacities of HRMVECs were significantly suppressed following treatment with the STAT5 inhibitor. Our findings demonstrate that STAT5 signaling promotes RNV progression by enhancing endothelial cell survival and angiogenic functions.