Circulating soluble fms-like tyrosine kinase-1 is placentally derived in normal pregnancy: First in vivo evidence
Introduction
Soluble fms-like tyrosine kinase-1 (sFlt-1) is an anti-angiogenic factor that increases significantly in the maternal circulation during normal pregnancies and even more so in preeclampsia (PE) [1]. Its physiologic role in normal pregnancies is not known. However, when present in extremely high levels, it causes widespread endothelial dysfunction leading to the development of PE and it is now used as a circulating biomarker for this disease. The study of placental and sFlt-1 biology, is fundamental for the understanding of preeclampsia. Numerous studies have shown in vitro sFlt-1 expression and secretion in normal and preeclampsia placentas (higher in PE placentas) [2]. Other sources of sFlt-1 have also been proposed such as smooth muscle cells, endothelial cells and PBMCs [3], [4]. Placental production has been assessed in vivo by comparing the uterine and peripheral sFlt-1 levels. These studies showed a gradient of sFlt-1 in preeclampsia patients (higher levels in uterine vein than periphery) but not in normal pregnancy [5], [6], [7]. This suggested that the placenta is an important source of sFlt-1 in preeclampsia but not in normal pregnancies. This was proposed to argue against placental production in the absence of PE. These studies did not a) adjust for placental location, b) interrogate postpartum levels or c) use automated assays. We set out to determine whether maternal sFlt-1 is placentally derived in normal pregnancy by accounting for these factors.
Section snippets
Methods
Ultrasound to assess placental location was performed prior to elective caesarean section in women with normal pregnancy course. We aimed to find patients with extreme lateral placentas where we could sample both uterine veins, and all patients who consented for the study had their placenta location recorded. Serum samples from the antecubital (peripheral) and uterine vein (UV) were collected during caesarean section prior to delivery of the fetus. Accessing bilateral samples was technically
Results
Seventeen (uterine and peripheral) paired samples were collected in total. Median gestational age was 39.4 (IQR 39.1-40) weeks. We first analysed bilateral samples from 3 patients with extreme lateral placentas. In these patients, sFlt-1 levels from ipsilateral samples were consistently higher than from contralateral ones (Fig. 1A). In order to further validate the hypothesis that placentally derived factors show a concentration difference between the ipsilateral and contralateral side, we
Discussion
We first demonstrated that, in cases of extreme lateral placentas, samples acquired from the uterine vein nearest to the placenta (ipsilateral) have a higher concentration than the contralateral vessel. The likely placental origin was further confirmed by the concomitant measurement of beta-HCG. These samples also showed that there is an overall sFlt-1 gradient between the uterine vein and the periphery. Accordingly, there was a significant difference in the sFlt-1 concentration between the
Funding sources
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declarations of interest
The authors report no conflict of interest.
Acknowledgments
We acknowledge support from the National Institute for Health Research to ASC and WC who are NIHR Academic Clinical Lecturer and Clinical Fellow respectively. The authors would like to acknowledge all the Obstetricians, Anesthesiologists and Research Midwifes who made this work possible.
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