APELA (apelin receptor early endogenous ligand) is a peptide hormone that functions as an endogenous ligand for the G-protein-coupled apelin receptor (APLNR/APJ), playing critical roles in cardiovascular development and homeostasis 12. APELA acts as a balanced agonist, activating both the Gi protein pathway and beta-arrestin pathway of APLNR; downstream effects include inhibition of cAMP production and activation of ERK intracellular effectors 3. Mechanistically, APELA promotes mesendodermal cell migration during early development and acts as a chemoattractant for angioblast migration during vasculogenesis 12. The peptide regulates sinus venosus endothelial cell migration to promote coronary vessel sprouting and facilitates placental vascular development through trophoblast invasion and spiral artery remodeling 1. Disease relevance is substantial across multiple conditions. APELA-knockout mice exhibit hypertensive disorder of pregnancy-like symptoms with elevated blood pressure due to defective placental angiogenesis; human genetic studies identified T-A haplotypes in APELA as disease-susceptibility markers for hypertensive disorders of pregnancy 4. Additionally, APELA gene therapy significantly reduced pulmonary artery pressure in rats by inhibiting vascular remodeling via KLF2/eNOs and BMPRII/SMAD4 pathways 5. High APELA expression correlates with poor glioblastoma patient survival and tumor grade, suggesting oncogenic potential 6. These findings position APELA/APJ signaling as a promising therapeutic target for cardiovascular diseases and age-related disorders 78.