G protein-coupled receptor GPR182 negatively regulates sprouting angiogenesis via modulating CXCL12-CXCR4 axis signaling

Angiogenesis is a critical process for tumor progression, regulated by various signaling pathways. Although antiangiogenic therapies targeting the VEGF pathway have shown potential, their effectiveness is inconsistent across different tumor types. GPR182, an endothelial cell-specific G protein-coupled receptor, is frequently downregulated in hypervascular tumors, but its specific role in angiogenesis has not been well defined. Our study reveals that GPR182 expression is markedly reduced in hepatocellular carcinoma (HCC) and inversely correlates with CD31, a pan-endothelial marker. In zebrafish embryos, Gpr182 deficiency resulted in enhanced angiogenic sprouting and hypervascularization, and GPR182-deficient human umbilical vein endothelial cells (HUVECs) showed increased migration and proliferation. At the molecular level, GPR182 acts as a decoy receptor, binding CXCL12 and regulating its gradient, which in turn suppresses CXCR4-mediated angiogenesis. The pharmacological blockade of CXCR4 with AMD3100 corrected the abnormal angiogenic phenotype in Gpr182-deficient zebrafish embryos and in the livers of a zebrafish HCC model. This work uncovers GPR182 as a negative regulator of angiogenesis, a key process in tumor growth and metastasis, and proposes that targeting GPR182 may offer a novel therapeutic approach for antiangiogenic strategies in cancer treatment.