Scutellarin attenuates hypoxia-induced retinal neovascularization through bidirectional modulation of the...

Scutellarin (SCU), a flavonoid with established pharmacological activity, exhibits anti-angiogenic and vascular-stabilizing effects in ischemic ocular diseases.

This study investigated its bidirectional modulation of the vascular endothelial growth factor(VEGF)/Angiopoietin (Ang)/Tie2 signaling pathway in retinal neovascularization (RNV) under hypoxic conditions and compared its efficacy with Faricimab, a dual-target angiogenesis inhibitor. A CoCl₂-induced hypoxic model in rat retinal microvascular endothelial cells (rRMECs) was used to evaluate proliferation, migration, and tube formation. Network pharmacology and molecular docking were employed to predict SCU targets and key signaling pathways. Western blotting and qRT-PCR validated its regulatory effects at the molecular level.

SCU significantly and dose-dependently suppressed rRMEC proliferation, migration, and tube formation under hypoxia, with effects comparable to those of Faricimab at higher concentrations. Network pharmacology identified 43 overlapping targets between SCU and RNV. Pathway enrichment analysis indicated involvement of VEGF, MAPK, and Ras signaling. Molecular docking showed strong binding of SCU to VEGF-A, Ang2, Tie2, and Vascular endothelial protein tyrosine phosphatase (VE-PTP). SCU downregulated pro-angiogenic factors (VEGF-A, Ang2, HIF-1α, VE-PTP) and upregulated vascular stability-related proteins (Ang1, Tie2, vascular endothelial cadherin (VE-cadherin)) at both mRNA and protein levels.

These results suggest that SCU exerts a dual regulatory effect on retinal neovascularization by simultaneously inhibiting pathological angiogenesis and enhancing vascular stabilization via the VEGF/Ang/Tie2 signaling pathway. Its mode of action complements and extends the mechanism of Faricimab, supporting its potential as a promising natural candidate for retinal vascular disease therapy.