Abstract
Pre-eclampsia is associated with altered maternal and placental vascular reactivity. Kv7 channels (encoded by KCNQ 1–5 genes) are a potential contributor to the regulation of vascular tone in CPAs (chorionic plate arteries) during normal pregnancy. The aim of this study is to establish the expression profile of KCNQ subunits in CPAs taken from women with preeclampsia or normotensive women and to examine the functional relevance of the Kv7 channels on an altered expression profile of KCNQ subunits. The effects of Kv7 channel modulators on CPAs were investigated by tension measurement. Quantitative PCR experiments were used to analyze the expression of KCNQ genes. Western blotting and immunofluorescence were both used to analyze the protein expression of Kv7 channels. Finally, in CPAs from normotensive women, the Kv7 channel blocker XE991 increased arterial basal tone and U46619-induced contraction, and pre-contracted CPAs (10−7 M U46619) exhibited significant relaxation following treatment with Retigabine(Kv7.2–7.5 activator) and BMS-204352(Kv7.2–7.5 activator). However, ICA-27243(selective KCNQ2 and KCNQ3 activator) and ML277(selective KV7.1 activator) had no significant effect on tension in the pre-contracted CPAs. Conversely, compared with CPAs from normotensive women, the effects of XE991 on basal tone and agonist (U46619)-induced contractions in CPAs from women with preeclampsia were markedly attenuated. Moreover, the relaxation effects of Retigabine and BMS-204352 on pre-contracted CPA vessels from women with pre-eclampsia were also markedly down-regulated. Interestingly, the relaxation ability of ICA-27243 in pre-contracted CPA vessels in women with pre-eclampsia was enhanced. The mRNA of KCNQ3 was specifically up-regulated, whereas those for KCNQ4 and KCNQ5 were down-regulated in CPAs from women with pre-eclampsia compared with those in normotensive women. Similar observations were found in a subsequent analysis of protein expression of KCNQ genes 3–5. Thus, down-regulated Kv7 channel function in tension regulation of CPAs in women with pre-eclampsia could be associated with considerably altered expression profiles of Kv7 subunits.
Highlights
Pre-eclampsia is currently the most common and significant complication in obstetrics, complicating 3–5% of all pregnancies [1]
Because the mRNA levels of KCNQ genes 3–5 were markedly altered in Chorionic plate arteries (CPAs) from pre-eclampsia women compared with CPAs from normotensive women, we investigated whether this difference was maintained at the protein level
Our study find that functional Kv7 channels in human CPAs since firstly XE991 significantly increased basal and agonist-induced tone and secondly a range of specific Kv7 activators with key differences in chemical scaffolds significantly relaxed precontracted CPAs, which is consistent with observations in systemic vascular tissues from animals and humans [22,23,24,25,26,27]
Summary
Pre-eclampsia is currently the most common and significant complication in obstetrics, complicating 3–5% of all pregnancies [1]. The essential clinical presentation of preeclampsia traditionally entails new-onset hypertension and proteinuria occurring after 20 weeks of gestation in a previously normotensive woman. Maternal multiorgan dysfunction is included in the manifestations of this disorder, according to the new definition [2,3]. This disorder is universally combined with fetal growth restriction and preterm delivery. Women with complicated preeclampsia and their neonates are at increased risk of hypertension, metabolic disorders, cardiovascular disease and cardiovascular death in their future lives [4,5]
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