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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. [ABSTRACT FROM AUTHOR]

Conduit pulmonary arterial stiffening and the resultant increase in pulmonary vascular impedance have emerged as an important underlying driver of pulmonary arterial hypertension (PAH). Given that matrix deposition is central to vascular remodeling, we evaluated the role of the collagen cross-linking enzyme lysyl oxidase like 2 (LOXL2) in this study. Human pulmonary artery smooth muscle cells (PASMCs) subjected to hypoxia showed increased LOXL2 secretion. LOXL2 activity and expression were markedly higher in primary PASMCs isolated from the pulmonary arteries of the rat Sugen 5416 + hypoxia (SuHx) model of severe pulmonary hypertension (PH). Similarly, LOXL2 protein and mRNA levels were increased in the pulmonary arteries (PA) and lungs of rats with PH (SuHx and monocrotaline (MCT) models). Pulmonary arteries (PAs) isolated from the rats with PH exhibited hypercontractility to phenylephrine and attenuated vasorelaxation elicited by acetylcholine, indicating severe endothelial dysfunction. Tensile testing revealed a significant increase in PA stiffness in PH. Treatment with PAT-1251, a novel small-molecule LOXL2 inhibitor, improved active and passive properties of the PA ex vivo. There was an improvement in right heart function as measured by right ventricular pressure volume loops in vivo with PAT-1251. Importantly, PAT-1251 treatment ameliorated PH, resulting in improved pulmonary artery pressures, right ventricular remodeling, and survival. Hypoxia-induced LOXL2 activation is a causal mechanism in pulmonary artery stiffening in PH and pulmonary artery mechanical and functional decline. LOXL2 inhibition with PAT-1251 could be a promising approach to improve pulmonary artery pressures, right ventricular elastance, cardiac relaxation, and survival in PAH. NEW & NOTEWORTHY: Pulmonary arterial stiffening contributes to the progression of PAH and the deterioration of right heart function. This study shows that LOXL2 is upregulated in rat models of PH. LOXL2 inhibition halts pulmonary vascular remodeling and improves PA contractility, endothelial function, and PA pressure, resulting in prolonged survival. Thus, LOXL2 is an important mediator of PA remodeling and stiffening in PH and a promising target to improve PA pressures and survival in PH. [ABSTRACT FROM AUTHOR]

Baroreceptor reflex Blood pressure (BP), the major determinant of organ perfusion, is tightly regulated by negative feedback systems to ensure homeostasis in the event of cardiovascular stress. For example, gravity, [...], Mechanical stretch of baroreceptors in the wall of the aortic arch and carotid sinus initiates autonomic reflexes to change heart rate and blood pressure for cardiovascular homeostasis. In this issue of the JCI, Lu et al. show that tentonin 3 (TTN3), a recently identified stretch-sensitive ion channel, was present at the vagus afferent nerve endings innervating the aortic arch to function as a baroreceptor. This study expands the molecular profiles of baroreceptors and provides new insights into molecular mechanisms underlying the regulation of cardiovascular functions through baroreceptor function.