Virtual Presentation SRB Virtual Awards 2020

miR-155 controls the efficiency of placental development through the Angiotensin Type 1 Receptor (#1)

Anya L Arthurs 1 , Eugenie R Lumbers 2 , Celine Corbisier de Meaultsart 2 , Sarah Robertson 3 , John Schjenken 2 3 , Kirsty G Pringle 2
  1. Flinders University, Bedford Park, SA, Australia
  2. Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia
  3. University of Adelaide, Adelaide, SA, Australia

The angiomiR miR-155 has been implicated in the development of both healthy and abnormal placentae, yet the precise role is unknown. A known mRNA target of miR-155 is angiotensin II receptor 1 (AT1R). Increasing placental AT1R is pro-proliferative and promotes placentation, therefore we investigated the hypothesis that AT1R regulation by miR-155 controls placental growth.

To determine the effects of miR-155 on proliferation of trophoblasts, HTR-8/SVneo cells were cultured with a miR-155 mimic at varying concentrations. Increasing doses of the miR-155 mimic significantly reduced both AT1R mRNA abundance (by 60%) and trophoblast cell proliferation (by up to 90%) as assessed by qPCR and the xCELLigence RTCA system, respectively.

To support these in vitro experiments, we utilised a miR-155-/- mouse model to measure effects of miR-155 in the placenta. Pregnant miR-155+/+ and miR-155-/- mice were sacrificed at post-coital day 17.5 and tissues were collected. Placentae and fetuses were weighed, prior to immunohistochemistry and harvesting for RNA and protein. miR-155 was undetectable by qPCR in placentae from miR-155-/- dams, with AT1R mRNA and protein shown to be significantly increased (n=4-9 placentae/dam, 10 dams total).

Placentae from miR-155-/- dams showed significantly larger labyrinth zones and labyrinth:placental area ratios compared with controls, however placental weight was unchanged. Moreover, miR-155-/- dams produced pups that were significantly heavier, with unchanged fetal:placental weight ratios compared with control mice.

This study showed that placental miR-155 reduces AT1R mRNA and protein abundance, and decreases trophoblast proliferation. Knockout of miR-155 amplified labyrinth zone growth, increasing substrate transfer to the fetus, and subsequently increasing fetal weight. This shows that miR-155 controls placental growth by suppressing AT1R. 

miR-155 regulation is clearly essential for normal placental, and hence fetal, growth. Since miR-155 is dysregulated and secreted in preeclampsia, it may be a useful biomarker or therapeutic target for early detection and resolution.

  1. Cheng, W., Liu T, Jiang F, Liu C, Zhao X, Gao Y, Liu Z. (2011). "microRNA-155 regulates angiotensin II type 1 receptor expression in umbilical vein endothelial cells from severely pre-eclamptic pregnant women." International Journal of Molecular Medicine 27: 393-399.
  2. Walther, T., Jank A, Heringer-Walther S, Horn LC, Stepan H. (2008). "Angiotensin II Type 1 Receptor Has Impact on Murine Placentation." Placenta 29(10): 905-909.
  3. Pineles, B., Romero R, Montenegro D, Tarca AL, Han YM, Kim YM, Draghici S, Espinoza J, Kusanovic JP, Mittal P, et al. (2007). "Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia." Am J Obstet Gynecol 196(3): 261-266.