Fibronectin and JMJD6 Signature in Circulating Placental Extracellular Vesicles for the Detection of Preeclampsia

Preeclampsia (PE) is a major obstetric complication that is challenging to predict. Currently, there are limited tools to assess placental health/function in crucial gestational periods for diagnosis and early prediction. The glycoprotein fibronectin (FN) is augmented in PE placentae, and associated with reduced activity of JMJD6, an oxygen sensor that regulates placental FN processing. Evidence implicates placenta-derived small extracellular vesicles (sEVs) in the pathogenesis of pregnancy-associated disorders. Here, we examined the utility of FN and JMJD6 in placental sEVs as putative markers for early- and late-onset PE (E-PE and L-PE). Maternal plasma was obtained from venous blood collected longitudinally during pregnancy (10-14, 16-22, and 26-32 weeks of gestation and at delivery) in normotensive term control, preterm control, L-PE, E-PE, and gestational hypertensive individuals. Placenta-derived sEVs were isolated and their FN and JMJD6 content and JMJD6 activity were measured. In women that went on to develop preeclampsia, FN content of circulating placental sEVs was significantly elevated as early as 10 to 14 weeks of gestation and remained augmented until the time of delivery. This was accompanied by a depletion in JMJD6 content. Multivariate receiver operating characteristic analysis revealed high predictive power for FN and JMJD6 as early markers of E-PE and L-PE. In vitro, hypoxia or JMJD6 loss promoted FN accumulation in sEVs that was reverted on restoring cellular iron balance with the natural compound, Hinokitiol. Elevated FN, along with diminished JMJD6 in circulating placental sEVs, serves as an early molecular signature for the detection of different hypertensive disorders of pregnancy and their severity.