YC-1 reduces placental sFlt-1 and soluble endoglin production and decreases endothelial dysfunction: A possible therapeutic for preeclampsia
Introduction
Preeclampsia is a leading cause of maternal and perinatal mortality and morbidity (Redman and Sargent, 2005, Sibai et al., 2005). A crucial step in the pathogenesis is the release of anti angiogenic factors sFlt-1 (Maynard et al., 2003) and soluble endoglin (Venkatesha et al., 2006) into the maternal vasculature. This leads to widespread endothelial dysfunction and multisystem organ injury and failure. Currently there is no medical treatment and delivery at preterm gestations is often required to stop disease progression (Chaiworapongsa et al., 2014a). A medical therapeutic that stabilizes the disease process and allows pregnancies to safely continue, could significantly improve fetal and maternal outcomes (Chaiworapongsa et al., 2014b).
The etiology of preeclampsia is believed to stem from abnormal placental trophoblast invasion into maternal uterine spiral arteriols (Redman and Sargent, 2005, Sibai et al., 2003). This is thought to result in inadequate placental perfusion and hypoxia and leads to increased secretion of sFlt-1 and soluble endoglin (sENG) (Redman and Sargent, 2005, Karumanchi and Bdolah, 2004). This premise is supported by the clinical observation that patients with preeclampsia have a 50–70% reduction in uteroplacental blood flow (Lunell et al., 1984). Furthermore, restricting uterine blood flow in pregnant rats increases serum sFlt-1 and induces a preeclamptic-like phenotype (Granger et al., 2006). Hypoxic-inducible factor-1α (HIF1α) is the master regulator of the hypoxic response and has been found to be increased in preeclampsia (Caniggia and Winter, 2002, Rajakumar et al., 2004). Over-expression of HIF1α in pregnant mice recapitulates the preeclamptic phenotype including elevated circulating sFlt-1, hypertension and proteinuria (Tal et al., 2010). Therefore, a medication that blocks HIF1α could represent a therapeutic strategy for preeclampsia, as it may decrease placental production of sFlt-1 and sENG (Rana et al., 2014).
Endothelial dysfunction is responsible for the maternal preeclampsia phenotype and results in widespread end organ injury (Borzychowski et al., 2006). It is likely caused by an increase in circulating antiangiogenic factors sFlt-1 and sENG and an elevation in the potent vasoconstrictor endothelin 1 (Nishikawa et al., 2000) and pro-inflammatory cytokine TNFα (Sanchez-Aranguren et al., 2014). Thus, a drug that can reduce endothelial dysfunction may also be useful as a treatment for preeclampsia.
YC1 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole is a cardiovascular medication (Stasch et al., 2011) that quenches endothelial dysfunction (Galle et al., 1999) by inducing nitric oxide (Wohlfart et al., 1999), a potent vasodilator, and also independently activates its receptor guanylyl cyclase (Ramos-Espiritu et al., 2011). It has also been found to inhibit HIF1α (Yeo et al., 2003). Given its known vasoprotective properties and its ability to block HIF1α we hypothesize that YC-1 may reduce sFlt-1 and sENG secretion from primary human pregnancy tissues and rescue the endothelial dysfunction characteristic of preeclampsia. We therefore undertook functional studies in primary human tissues to examine the potential of YC-1 as a novel treatment for preeclampsia.
Section snippets
Placenta explant culture
Human placental tissue was collected from three women with normal pregnancy at term and also three women with severe early onset preeclampsia (delivered at ≤34 weeks gestation). Preeclampsia was defined using the 2013 American College of Obstetricians and Gynecologists (ACOG) guidelines: the presence of hypertension >140/90 on two occasions 4 h apart and any of the following: proteinuria >300 mg/day, renal insufficiency, impaired liver function, thrombocytopenia or visual disturbance (ACOG, 2013
Theory
We hypothesise that YC-1, a HIF1α inhibitor and guanylyl cyclase activator, will reduce sFlt-1 and sENG secretion and improve endothelial dysfunction.
YC1 reduces sFlt-1 secretion from primary human tissues
Firstly we examined the effect of YC-1 on sFlt-1 secretion from primary trophoblasts and from placental explants obtained from women undergoing a term normal pregnancy and from patients diagnosed with preterm preeclampsia. YC-1 dose dependently reduced sFlt-1 secretion from primary trophoblasts (Fig. 1A). There was no change to sFlt-1 secretion from normal placental explants treated with YC-1 when cultured at 8% oxygen (Fig. 1B) however a reduction in secretion occurred when cultured at 1%
Discussion
Preeclampsia is a devastating complication of pregnancy with no medical treatment. A drug that can reduce placental secretion of anti-angiogenic factors sFlt-1 and sENG and rescue endothelial dysfunction may stabilize the disease process and reduce subsequent maternal and perinatal mortality and morbidity. Placental hypoxia and elevation of HIF1α is an upstream event in the pathogenesis of preeclampsia (Karumanchi and Bdolah, 2004) that leads to increased secretion of sFlt-1 and sENG and
Conclusion
The data presented suggest that the effects of YC-1 on sFlt1 and sENG involve modulation of HIF1α expression. Importantly other mechanisms may also contribute to the mode of action of YC-1. Elucidation of other pathways downstream of YC-1, as well as other inhibitors of HIF1α, may lead to additional approaches for preeclampsia therapy.
Sources of funding
This work was funded by The National Health and Medical Research Council of Australia (NHMRC; #1048707, #1046484) and an Arthur Wilson RANZCOG scholarship. FB was supported by an Australian Postgraduate Award and an AVANT scholarship. The NHMRC provided salary support (#1050765 to ST #1062418 to TKL, #628927 to NJH). The funders had no role in study design, data collection, analysis, decision to publish or helped to prepare the manuscript.
Acknowledgments
We would also like to thank the research midwives, Gabrielle Pell, Genevieve Christophers, Rachel Murdoch and Debra Jinks, and patients at Mercy Hospital for Women for participating in this research.
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