Succinate Mediates Immune‐Angiogenic Response by Activating Macrophage M2 Polarization in Oxygen‐Induced Retinopathy

Retinal neovascularization (RNV) is a serious pathological process that destroys the normal structure of the retina and leads to vision loss. Succinate, an important product of the tricarboxylic acid (TCA) cycle, has recently been discovered to play essential functions in inflammation and cardiovascular disease. In this research, we discovered that succinate can regulate macrophage phenotyping via the G protein-coupled receptor 91 (GPR91) on the surface of macrophages. The induction of succinate polarized macrophages toward the M2 phenotype. Furthermore, studies revealed that succinate influences macrophage phenotypic direction by modulating the SIRT1/AMPKα pathway. Ex527 inhibited macrophage M2-type polarization after succinate induction, preventing abnormal retinal vascular development in oxygen-induced retinopathy (OIR) mice. Interestingly, we noticed an increase in RBP4 in macrophage supernatant after succinate induction. Exogenous RBP4 elevated VEGFR2 expression and tube formation in vascular endothelial cells. Meanwhile, the increase in VEGFR2 is possibly attributed to endocytosis. In summary, succinate regulates macrophage M2 polarization via the SIRT1/AMPKα pathway and mediates RNV formation. It also influences endothelial cell angiogenic capacity by promoting VEGFR2 internalization.