Macrophage-Secreted U2AF1 Orchestrates Coronary Artery Angiogenesis to Facilitate Myocardial Infarction Repair Through the Regulation of Yap1 Variable Splicing

Myocardial infarction (MI) is characterized by focal necrosis resulting from prolonged myocardial ischemia due to coronary artery obstruction. Vascular reconstruction following MI is crucial for improving cardiac function and preventing recurrent infarction. This study investigates the interaction between macrophages and endothelial cells in angiogenesis mediated by nicotinamide mononucleotide (NMN)-induced secretion of macrophage-derived exosomes. We focus on the role of U2 small nuclear RNA auxiliary factor 1 (U2af1 ) gene, a member of the splicing factor serine and arginine ( SR ) gene family, in the regulation of angiogenesis. Through cardiac ultrasound, Masson staining, 2,3,5-triphenyltetrazolium chloride (TTC) staining, Microfil vascular perfusion, and cluster of differentiation 31 (CD31) immunofluorescence staining, extracellular vesicles from NMN-stimulated macrophages were shown to exert a protective effect in MI, with proteomic analysis identifying U2AF1 as a candidate protein involved in MI protection. Plasma U2AF1 levels were measured in 70 MI patients, revealing significantly lower levels in individuals with poor coronary collateral vessel (CCV; Rentrop scores 0–1) than in those with good CCV (Rentrop scores 2–3). In both myocardial and hindlimb ischemia mouse models, overexpression of endothelial cell-specific adenoviral U2AF1 promoted angiogenesis in the heart and hindlimbs and improved cardiac function after MI. Mechanistic studies demonstrated that U2AF1 regulates the alternative splicing (AS) of Yes1-associated transcriptional regulator ( Yap1 ) gene, influencing post-MI angiogenesis and cardiac function recovery. Collectively, our clinical findings suggest that U2AF1 may serve as a therapeutic target for coronary collateral angiogenesis following MI. Given the low immunogenicity and high biosafety of exosomes, this study provides a foundational basis and translational potential for exosome-based therapies in MI treatment.