sema-HUVEC

Secreted proteins are crucial for angiogenesis and cardiac repair following myocardial infarction (MI). Although PCSK5 (proprotein convertase subtilisin/kexin 5) is essential for heart development, its role in MI is unexplored. 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 the 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. Single-nucleus RNA sequencing showed that PCSK5 increased capillary endothelial cells in the ischemic mouse hearts. PCSK5 was found to directly cleave vascular endothelial growth factor A (VEGFA), activating its signaling and promoting angiogenic activity. The residues Arg158 and Asn164 of PCSK5 were crucial for its function. In MI patients, PCSK5 plasma levels positively correlated with VEGFA and glucagon-like peptide-1. Semaglutide enhanced PCSK5 expression through the transcription factor ETS1, enhancing angiogenic activity in ECs. It also 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 and suggested its potential as a therapeutic target for ischemic diseases.