Abstract
In preeclampsia, widespread maternal endothelial dysfunction is often secondary to excessive generation of placental-derived anti-angiogenic factors, including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), along with proinflammatory cytokines such as tumour necrosis factor-α (TNF-α) and activin A, understanding of which offers potential opportunities for the development of novel therapies. The antimalarial hydroxychloroquine is an anti-inflammatory drug improving endothelial homeostasis in lupus. It has not been explored as to whether it can improve placental and endothelial function in preeclampsia. In this in vitro study, term placental explants were used to assess the effects of hydroxychloroquine on placental production of sFlt-1, sEng, TNF-α, activin A, and 8-isoprostane after exposure to hypoxic injury or oxidative stress. Similarly, human umbilical vein endothelial cells (HUVECs) were used to assess the effects of hydroxychloroquine on in vitro markers of endothelial dysfunction. Hydroxychloroquine had no effect on the release of sFlt-1, sEng, TNF-α, activin A, or 8-isoprostane from placental explants exposed to hypoxic injury or oxidative stress. However, hydroxychloroquine mitigated TNF-α-induced HUVEC production of 8-isoprostane and Nicotinanamide adenine dinucleotide phosphate (NADPH) oxidase expression. Hydroxychloroquine also mitigated TNF-α and preeclamptic serum-induced HUVEC monolayer permeability and rescued the loss of zona occludens protein zona occludens 1 (ZO-1). Although hydroxychloroquine had no apparent effects on trophoblast function, it may be a useful endothelial protectant in women presenting with preeclampsia.
Highlights
Preeclampsia complicates 3%–5% of all pregnancies and remains one of the leading causes of maternal and perinatal morbidity and mortality [1]
We hypothesize that hydroxychloroquine may confer beneficial effects in women diagnosed with preeclampsia by reducing placental production of potentially deleterious mediators, improving the overall maternal endothelial homeostasis
Hypoxia significantly increased the secretion of soluble fms-like tyrosine kinase-1 (sFlt-1) (Figure 1a, p = 0.02), soluble endoglin (sEng) (Figure 1b, p = 0.02), and tumour necrosis factor-α (TNF-α) (Figure 1c, p = 0.02) from explant cultures after 24 h incubation
Summary
Preeclampsia complicates 3%–5% of all pregnancies and remains one of the leading causes of maternal and perinatal morbidity and mortality [1]. Inadequate trophoblast invasion and failure of maternal spiral arterial remodeling leads to impaired placental development, including exposure to chronic progressive ischaemia–reperfusion injury characterized by evidence of excessive oxidative stress This induces excessive placental release of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), coupled with inflammatory cytokines including tumour necrosis factor-α (TNF-α) and activin A [5,6,7,8]. These various factors target the maternal vasculature and contribute significantly to the widespread maternal vascular dysfunction, which is often associated with oxidative injury [9,10,11,12]. Dysfunctional cells of the vasculature are characterized by increased endothelial cell permeability, altered distribution of endothelial junctional proteins, and reduced endothelium-dependent relaxation [13,14]
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