PCSK5 (proprotein convertase subtilisin/kexin 5) is essential for heart development. However, its role in myocardial infarction (MI) remains unexplored. In this study, we found that the plasma levels of PCSK5 were elevated in MI patients and exhibited potential in predicting cardiac function improvement. PCSK5 expression was upregulated in cardiac endothelial cells (ECs) of MI patients. Pcsk5 deficiency in ECs impaired angiogenesis and cardiac recovery post-MI, and delayed tissue repair following hindlimb ischemic injury in male mice. In contrast, the endothelial-specific Pcsk5 delivery enhanced angiogenesis and cardiac function post-MI. Mechanistically, PCSK5 directly cleaved VEGFA, activating its signaling and promoting angiogenic activity. The residues Arg158 and Asn164 of PCSK5 were crucial for its function. Semaglutide increased vascular densities and cardiac function post-MI, partially through EC-derived Pcsk5 in male mice. This study identified PCSK5 as a pro-angiogenic factor secreted by ECs, with the potential to become a therapeutic target for ischemic diseases.