Abstract
Preeclampsia is a pregnancy complication associated with elevated placental secretion of anti-angiogenic factors, maternal endothelial dysfunction and organ injury. GATA2 is a transcription factor expressed in the endothelium which regulates vascular homeostasis by controlling transcription of genes and microRNAs, including endothelial miR126. We assessed GATA2 and miR126 in preeclampsia. Whole blood circulating GATA2 mRNA and miR126 expression were significantly decreased in women with established early-onset preeclampsia compared to gestation-matched controls (p = 0.002, p < 0.0001, respectively). Using case-control groups selected from a large prospective cohort, whole blood circulating GATA2 mRNA at both 28 and 36 weeks’ gestation was significantly reduced prior to the clinical diagnosis of preeclampsia (p = 0.012, p = 0.015 respectively). There were no differences in GATA2 mRNA or protein expression in preeclamptic placentas compared to controls, suggesting the placenta is an unlikely source. Inducing endothelial dysfunction in vitro by administering either tumour necrosis factor-α or placenta-conditioned media to endothelial cells, significantly reduced GATA2 mRNA expression (p < 0.0001), suggesting the reduced levels of circulating GATA2 mRNA may be of endothelial origin. Circulating GATA2 mRNA is decreased in women with established preeclampsia and decreased up to 12 weeks preceding onset of disease. Circulating mRNAs of endothelial origin may be a novel source of biomarker discovery for preeclampsia.
Highlights
Preeclampsia is a multi-system disease that complicates 3–8% of pregnancies worldwide each year and 10–15% of direct maternal deaths are attributable to preeclampsia or eclampsia[1]
Given circulating GATA2 mRNA levels were changed among women with established preeclampsia, we examined whether levels were differentially expressed prior to the development of late-onset disease
We performed a nested case-control study where we measured circulating GATA2 mRNA levels at 28 weeks in participants who went on to develop late-onset preeclampsia and controls and similar groups at 36 weeks’ gestation
Summary
Preeclampsia is a multi-system disease that complicates 3–8% of pregnancies worldwide each year and 10–15% of direct maternal deaths are attributable to preeclampsia or eclampsia[1]. The origin of early-onset preeclampsia most likely lies in the poorly perfused placenta secreting elevated levels of placental factors such as anti-angiogenic molecules and inflammatory cytokines[3] These cause widespread endothelial cell dysfunction[4] and vascular injury leading to the end organ damage seen in clinical disease. A first trimester test has been identified that combines, circulating placental growth factor (PIGF), uterine artery Doppler flow measured by ultrasound (increased resistance is associated with early placental dysfunction) and the mother’s mean arterial pressure[6] This test is sensitive in predicting early onset preeclampsia and identifying mothers who screen high risk in this test may allow obstetricians to intervene with increased monitoring to avoid the consequences of preeclampsia[7]. MiR126 has been shown to regulate vascular endothelial growth factor A (VEGF-A)[18], which has specific endothelial cell functions such as promotion of angiogenesis, and growth of endothelial cells
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