miR-155 suppresses angiotensin II type 1 receptor synthesis during placental morphogenesis

Several microRNAs play vital roles in placental development. miR-155 has been implicated in placental development and can directly interact with a variety of targets, including angiotensin type II receptor 1 (AT₁R) (Agtr1) mRNA. The AT₁R is pro-proliferative and promotes early placental development. We therefore tested the hypothesis that miR-155 downregulates Agtr1 mRNA expression and impairs placental development. Placentae and fetuses from wild-type C57Bl/6 mice (miR-155^+/+, control) and C57Bl/6 mice with a null mutation in miR-155 (miR155^-/-) were mated with males of the same genotype and analyzed on gestational day 18.5, when placental morphology and miR-155 and AGTR1 expression were assessed. Additionally, HTR8/SVneo cells were cultured with a miR-155 mimic to determine the effects on trophoblast proliferation, migration and invasion. miR-155^-/- dams produced significantly heavier pups with unchanged placental weights and fetal-to-placental weight ratios. Placentae from miR-155^-/- dams had significantly larger labyrinth zones and labyrinth-to-placental area ratios than controls, with altered stereological parameters. Placental Agtr1 mRNA and AGTR1 protein levels were significantly increased in miR-155^-/- dams. Finally, in vitro treatment in human HTR-8/SVneo cells with the miR-155 mimic increased miR-155 expression, decreased AGTR1 mRNA levels and decreased the rates of trophoblast cell proliferation, migration and invasion. Thus, miR-155 is demonstrated to attenuate placental development in mice. We propose that this is at least partly due to its effects on the AT₁R.