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.

Background: Preeclampsia is a serious pregnancy complication affecting 5% to 8% of pregnancies globally. preeclampsia is a leading cause of maternal and neonatal morbidity and death. Despite its prevalence, the underlying mechanisms of preeclampsia remain unclear. This study investigated the role of vasorin in preeclampsia pathogenesis by examining its levels in extracellular vesicles ( EVs ) and effects on vascular function. Methods and Results: We conducted unbiased proteomics on urine‐derived EVs from women with severe preeclampsia and normotensive pregnancies, identifying differentially abundant proteins. Vasorin expression levels were measured in urinary EVs, plasma EVs, and placental tissue. EVs were generated from human and murine placental explants. Vascular functions were assessed using murine aortic rings and human aortic endothelial cells. Vasorin expression was manipulated in human aortic endothelial cells via overexpression and knockdown followed by RNA sequencing. One hundred twenty proteins showed ≥±1.5‐fold regulation ( P <0.05) between severe preeclampsia and NTP. Vasorin levels decreased in severe preeclampsia in urinary EVs, plasma EVs, and placental tissue. Vasorin levels increased with gestational age in murine pregnancy and were diminished in a murine model of preeclampsia. Severe preeclampsia and murine preeclampsia EVs impaired human aortic endothelial cell migration and inhibited murine aortic ring vasorelaxation. Vasorin overexpression counteracted these effects. RNA sequencing showed that vasorin manipulation in human aortic endothelial cells differentially regulated hundreds of genes linked to vasculogenesis, proliferation, migration, and apoptosis. Conclusions: The data suggest that vasorin, delivered to the endothelium via EVs, regulates vascular function and that the loss of EV vasorin may be one of the mechanistic drivers of preeclampsia.

Background Preeclampsia (PE) is a serious pregnancy complication affecting 5-8% of pregnancies globally. It is a leading cause of maternal and neonatal morbidity and mortality. Despite its prevalence, the underlying mechanisms of PE remain unclear. This study aimed to determine the potential role of vasorin (VASN) in PE pathogenesis by investigating its levels in extracellular vesicles (EV) and its effects on vascular function. Methods & Results We conducted unbiased proteomics on urine-derived EV from severe PE (sPE) and normotensive pregnant women (NTP), identifying differential protein abundances. Out of one hundred and twenty proteins with ≥ ±1.5-fold regulation at P<0.05 between sPE and NTP, we focused on Vasorin (VASN), which is downregulated in sPE in urinary EV, in plasma EV and in the placenta and is a known regulator of vascular function. We generated EV with high VASN content from both human and murine placenta explants (Plex EV), which recapitulated disease-state-dependent effects on vascular function observed when treating murine aorta rings (MAR) or human aortic endothelial cells (HAEC) with murine or human plasma-derived EV. In normal murine pregnancy, VASN increases with gestational age (GA), and VASN is decreased in plasma EV, in placenta tissue and in Plex EV after intravenous administration of adenovirus encoding short FMS-like tyrosine kinase 1 (sFLT-1), a murine model of PE (murine-PE). VASN is decreased in plasma EV, in placenta tissue and in EV isolated from conditioned media collected from placenta explants (Plex EV) in patients with sPE as compared to NTP. Human sPE and murine-PE plasma EV and Plex EV impair migration, tube formation, and induces apoptosis in human aortic endothelial cells (HAEC) and inhibit acetylcholine-induced vasorelaxation in murine vascular rings (MAR). VASN over-expression counteracts the effects of sPE EV treatment in HAEC and MAR. RNA sequencing revealed that over-expression or knock down of VASN in HAEC results in contrasting effects on transcript levels of hundreds of genes associated with vasculogenesis, endothelial cell proliferation, migration and apoptosis. Conclusions The data suggest that VASN, delivered to the endothelium via EV, regulates vascular function and that the loss of EV VASN may be one of the mechanistic drivers of PE. CLINICAL PERSPECTIVE What is New VASN in circulating plasma EV in sPE is reduced compared with VASN content in plasma EV of gestational age-matched pregnant women. VASN is encapsulated and transported in EV and plays a pro-angiogenic role during pregnancy. VASN should be explored both for its pro-angiogenic mechanistic role and as a novel biomarker and potential predictive diagnostic marker for the onset and severity of PE. What Are the Clinical Implications? VASN plays a role in maintaining vascular health and the normal adaptive cardiovascular response in pregnancy. A decrease of VASN is observed in sPE patients contributing to cardiovascular maladaptation. Strategies to boost diminished VASN levels and/or to pharmacologically manipulate mechanisms downstream of VASN may be explored for potential therapeutic benefit in PE. The decrease in EV-associated VASN could potentially be used as a (predictive) biomarker for PE.

Preeclampsia (PE) remains a leading cause of maternal and fetal morbidity and mortality worldwide, yet the precise molecular mechanisms driving its pathology are not fully understood. Recent research has established extracellular vesicles (EVs) as critical mediators in the development of PE-related vascular dysfunction. These nanosized, lipid-bound particles are secreted by cells and serve as a sophisticated system of intercellular communication, carrying functionally active cargo—including proteins, nucleic acids, and lipids—that can modulate physiological and pathological processes via autocrine, paracrine, and endocrine signaling. While the role of EVs-mediated communication in PE has been extensively studied, the specific functions of individual protein components within this cargo remain largely unexplored. Vasorin (VASN), a known regulator of the TGF-β signaling pathway, is a promising candidate for investigation in pregnancy disorder. This review synthesizes existing evidence on VASN's role in PE and discusses its potential contributions to disease pathogenesis. We will highlight the critical need for future research to elucidate VASN's function and evaluate its activity as a promising new therapeutic strategy for a spectrum of pregnancy-related disorders.