Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and placental vascular dysfunction plays a role in the pathogenesis and can persist into the postpartum period. Potential abnormalities include impaired placentation, incomplete spiral artery remodeling, and endothelial damage, which are further propagated by immune factors, mitochondrial stress, and an imbalance of pro- and antiangiogenic substances. While the field has progressed, current gaps in knowledge include detailed initial molecular mechanisms and effective treatment options. Newfound evidence indicates that vasopressin is an early mediator and biomarker of the disorder, and promising future therapeutic avenues include mitigating mitochondrial dysfunction, excess oxidative stress, and the resulting inflammatory state. In this review, we provide a detailed overview of vascular defects present during preeclampsia and connect well-established notions to newer discoveries at the molecular, cellular, and whole-organism levels.
Background: Preeclampsia (PreE) is a significant global health burden which impacts 10 million pregnancies annually resulting in over a half million lost lives. Mitochondrial damage has previously been demonstrated to be present in PreE. A novel relationship may exist between preeclampsia and mitochondrial damage via the release of cell-free mitochondrial DNA (cf-mtDNA). Previous work in models of systemic hypertension shows cf-mtDNA mediated activation of TLR9 to be a key part of disease development. We aim to evaluate the level of TLR9 activation and ROS production in patients with and without PreE. Methods: To investigate whether PreE plasma contains increased levels of cell free DNA that can activate TLR9, HEK-Blue TM -hTLR9 reporter cell line (Invivogen) was treated with 3% plasma from either control or PreE patients. The TLR9 activator ODN2006 served as positive control (Fig.1, A&B). To investigate whether PreE plasma can stimulate production of ROS, HUVECs were treated in similar fashion and ROS was evaluated using Mitosox TM (Fig. 1, C&D). Results: Cells treated with PreE plasma demonstrated a 1.7-fold increase in TLR9 activation vs control (p=0.005, Fig. 1A&B). In addition, Mitosox TM signal indicated a 1.8-fold increase in ROS in PreE vs. control (p=0.066, Fig. 1C&D). Conclusion: We conclude that plasma from PreE patients contains higher levels of cf-mtDNA that stimulates inflammation response via TLR9 that promotes mitochondrial ROS production. This mechanism may present a novel target for treatment of Pre-E.
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