Succinate-induced macrophage polarization and RBP4 secretion promote vascular sprouting in ocular neovascularization

Area of Science:

• Ophthalmology
• Immunology
• Metabolic pathways

Background:

• Pathological neovascularization is central to wet age-related macular degeneration (AMD), retinopathy of prematurity (ROP), and proliferative diabetic retinopathy (PDR).
• Macrophages (Mφs) are key immune cells involved in angiogenesis, but their interaction with the immune microenvironment during tip cell specialization is not fully understood.
• Succinate, a tricarboxylic acid cycle intermediate, was found to be elevated in wet AMD patients.

Purpose of the Study:

• To investigate the role of succinate in pathological neovascularization.
• To elucidate the mechanism by which succinate influences macrophage polarization and angiogenesis.
• To explore the involvement of the succinate receptor 1 (SUCNR1) and RBP4/VEGFR2 pathway in neovascularization.

Main Methods:

• Metabolomic analysis of wet AMD patients.
• In vitro and in vivo experiments using choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) models.
• Assessment of macrophage polarization (M2), vascular endothelial cell (EC) migration, invasion, and tubulation.
• Analysis of succinate-induced RBP4 release and its effect on VEGFR2 signaling.

Main Results:

• SUCNR1 expression and M2 polarization were observed in macrophages within abnormal vessels in CNV and OIR models.
• Succinate promoted M2 polarization via SUCNR1, enhancing EC migration, invasion, and tubulation, thereby promoting angiogenesis.
• Succinate stimulated macrophages to release RBP4, which in turn promoted endothelial sprouting and pathological angiogenesis through the VEGFR2 pathway.

Conclusions:

• Succinate acts as a novel vasculature-inducing factor in pathological neovascularization.
• Succinate modulates macrophage polarization and the RBP4/VEGFR2 pathway, crucial for tip cell specialization and pathological angiogenesis.
• Targeting the succinate pathway may offer new therapeutic strategies for neovascular eye diseases.