Placental extracellular vesicles from women with severe preeclampsia alter calcium homeostasis in cardiomyocytes: an ex vivo study.

Women with severe preeclampsia (sPE) exhibit a heightened risk of postpartum cardiovascular disease compared with those with normotensive pregnancies (NTP). Although placental extracellular vesicles (EVs) play a crucial role in feto-maternal communication, their impact on cardiomyocytes, particularly in the context of sPE, remains unclear. This study investigated the effect of sPE-associated placental EVs (sPE-Plex EVs) on cardiomyocyte calcium dynamics. We hypothesized that sPE-Plex EV mediates cardiomyocyte dysfunction by disrupting calcium signaling. EVs were isolated from plasma and placental explant culture (Plex) using precipitation methods and confirmed as Plex EVs by placental alkaline phosphatase (PLAP) activity and electron microscopy. Moreover, confocal microscopy confirmed the uptake of plasma EVs in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and Plex EVs by human AC-16 cardiomyocyte (hAC-16CM) cells. hiPSC-CM cells treated with sPE-EVs and hAC-16CM cells treated with sPE-Plex EVs exhibited significantly lower levels of stromal interaction molecule 1 (STIM1) and phospholamban (PLN) proteins compared with those treated with normotensive controls EVs, as confirmed by Western blot analysis. Treatment with sPE-Plex EVs also resulted in the downregulation of STIM1 and PLN proteins in murine cardiomyocyte (mCM) cells compared with treatment with NTP-Plex EVs. Our findings suggest that both plasma EVs and Plex EVs from sPE may alter calcium signaling in cardiac cells by downregulating calcium sensor proteins (STIM1 and PLN). Therefore, plasma EVs and Plex EVs from sPE pregnancies have adverse effects by altering calcium dynamics in hiPSC-CM, hAC-16CM, and mCM compared with normotensive control and potential impairment of cardiomyocyte function ex vivo.NEW & NOTEWORTHY This study unveils a novel link between the placenta and PE-linked heart dysfunction. We isolated and characterized placental EVs from pregnancies with sPE and normotensive controls. These plasma sPE-EVs, and sPE-Plex EVs disrupt calcium signaling in heart cells, potentially via reduced STIM1 and PLN proteins. This suggests both plasma sPE-EVs and sPE-Plex EVs cargo drive these disruptive effects. Identifying these cargo molecules (miRNAs or proteins) holds promise for new PE therapies targeting cardiac dysfunction.