Dynamics and biodistribution of cardiomyocyte-derived small extracellular vesicles following myocardial infarction: sex differences

Small extracellular vesicles (EVs) have become essential mediators of intercellular and interorgan communication in vivo, with significant therapeutic potential and prognostic value in cardiovascular diseases. Despite extensive research on exosomal cargoes and their biological effects, the in vivo dynamics and systemic distribution of cardiac-derived small EVs under pathological conditions remain poorly understood. This study used cardiac small EVs-tracking mice to profile the distribution and production of cardiomyocyte-derived small EVs following myocardial infarction (MI). We observed distinct temporal dynamics in cardiac small EVs uptake between males and females. In the heart, uptake increased markedly during the acute injury phase and declined during the healing phase in males, whereas it gradually declined in females, with both sexes showing preferential uptake by endothelial cells and leukocytes. The distribution of cardiac-derived small EVs in peripheral organs gradually decreased over time in male mice but followed different patterns in females. Females exhibited higher circulating levels of cardiac-derived small EVs and a more dynamic uptake into peripheral organs than males. Meanwhile, cardiac small EVs biogenesis tended to increase on <i>day 3</i> but significantly decreased by <i>day 14</i> in male MI hearts, whereas it increased in females as MI progressed. These findings provide the first comprehensive in vivo spatial and temporal map of endogenous cardiac small EVs dynamics after MI and its sexual dimorphism, laying a crucial foundation for future mechanistic studies.<b>NEW & NOTEWORTHY</b> Although extracellular vesicle (EV) contents and cargoes have attracted significant interest for their roles in intercellular and interorgan communication after myocardial infarction (MI), the endogenous dynamics and biogenesis of cardiac small EVs following MI, and their sexual differences, remain largely unknown. Here, we present the first in vivo characterization of cardiomyocyte-derived small EVs dynamics and sexual dimorphism in response to MI injury, establishing a framework and offering crucial mechanistic insights for future studies.