Conformational Dynamics of PKM2 Regulate Hypoxia-Induced Pathological Retinal Angiogenesis.

Area of Science:

• Ophthalmology
• Molecular Biology
• Biochemistry

Background:

• Anti-vascular endothelial growth factor (VEGF) therapies are not always effective for retinal neovascularization.
• Pyruvate kinase M2 (PKM2) is crucial in tumor growth but its role in retinal angiogenesis is unknown.
• Understanding new pathways is vital for treating retinal neovascular diseases.

Purpose of the Study:

• To explore the role of PKM2 conformational dynamics in pathological retinal neovascularization.
• To investigate how PKM2's structure influences retinal angiogenesis under hypoxic conditions.

Main Methods:

• Utilized an oxygen-induced retinopathy (OIR) mouse model and hypoxia-exposed human retinal microvascular endothelial cells (HRMECs).
• Evaluated PKM2 conformational dynamics using DASA-58, a small-molecule activator of PKM2 tetramerization.

Main Results:

• Hypoxia induced PKM2 monomerization, nuclear translocation, and interaction with HIF-1α, promoting angiogenic gene expression.
• DASA-58 treatment promoted PKM2 tetramer formation, inhibited nuclear translocation, suppressed HIF-1α signaling, and reduced retinal neovascularization.
• In vivo, DASA-58 treatment reduced neovascularization, vascular leakage, preserved retinal thickness, and improved visual function in OIR mice.

Conclusions:

• PKM2 conformational dynamics represent a novel regulatory mechanism in hypoxia-induced retinal neovascularization.
• Inducing PKM2 tetramer formation via DASA-58 presents a potential therapeutic strategy for neovascular eye diseases, including retinopathy of prematurity (ROP).