miR-155

miR-155 is upregulated in preeclamptic placentas [255]. This upregulation correlates inversely with the level of cysteine-rich protein 61(CYR61) [277], which is a factor secreted by di fferent cell types, including trophoblast, involved in promoting migration, invasion, angiogenesis and vascularisation [278,279]. miR-155 directly targets the 3-UTR of CYR61 mRNA with a perfect match, causing transcriptional and translational repression. In vitro experiments (HTR-8/SVneo trophoblast cell line) showed how miR-155 inhibits CYR61-mediated expression of VEGF, inhibiting trophoblast migration [277]. Decreased trophoblast-mediated secretion of VEGF would negatively affect angiogenesis and vascularisation in the site of placenta development.

miR-155 regulates trophoblast proliferation and migration also by directly targeting the cell cycle gene Cyclin D1 [172]. Cyclin D1 is involved in cell cycle progression, migration and invasion of trophoblast lineages, downregulated in preeclamptic placentas at both mRNA and protein levels [280–282]. In vitro studies have shown how miR-155 through direct targeting of the 3UTR of CyclinD mRNA downregulates mRNA and protein levels, negatively a ffecting migration, causing cell cycle arrest and decrease in proliferation in HTR-8/SVneo cells [42]. Exiting cell cycle is a step of terminal di fferentiation, which suggests how miR-155 overexpression, as found in preeclampsia, could lead to a premature di fferentiation of cytotrophoblasts, possibly inducing syncytialization. This phenomenon would cause depletion of the cytotrophoblast pool, accelerating placental aging.

In sum, miR-155 modulates proliferation, migration and invasion of trophoblasts and its expression can a ffect the phenotype of endothelial cells by negatively regulating VEGF release. miR-155 deregulation could have catastrophic consequences in placentation, deeply a ffecting trophoblast infiltration, vascularization and angiogenesis of the developing placenta.
