Human placental microRNAs and preeclampsia

Abstract

MicroRNAs are a class of noncoding small RNAs that regulate the expression of nearly 30% of all the human genes and participate in all fundamental cell processes. Genome-wide analysis has revealed that human placenta expresses more than 600 miRNA species, including placenta-specific ones with high levels of expression. Comparative analysis also has revealed many differentially expressed miRNAs with either high or low levels of expression in human placentas from normal versus preeclamptic pregnancies, indicating an important role of miRNAs in normal and pathological placental physiology. Although limited information is currently available as to how miRNA regulates human placental development and function, there are studies suggesting that preeclampsia-associated differentially expressed miRNAs possess critical roles in regulating placental development and function via targeting specific genes with diverse known functions. Herein we summarize the current findings regarding the expression of placental miRNAs and their function, especially in the trophoblast cells. We have recently found that the angiogenesis-associated miR-17-family miRNAs are upregulated in preeclamptic compared with normotensive placentas and they target the ephrin-B2/Eph receptor B4 (EPHB4) system. Because ephrin-B2 and EPHB4 has been previously shown to play a crucial role in trophoblast invasion into maternal spiral artery and vascular patterning during early human placental development, the miR-17-ephrin-B2/EPHB4 pathway seems to be a novel miRNA pathway for regulating normal and aberrant placental development during preeclampsia.

Keywords: microRNA; placenta; placentation; preeclampsia; pregnancy.

FIG. 1

Biogenesis and function of miRNAs. The miRNA biosynthesis begins with RNA polymerase II-dependent transcription of pri-miRNAs from miRNA genes that reside in the introns of their host genes. Pri-miRNAs fold into distinctive stem-loop precursors. In mammals, the long pri-miRNAs are first processed in the nucleus by a microprocessor complex that is composed of the RNase III endonuclease Drosha and a dsRNA-binding protein DGCR8, forming 60–70 nucleotide pre-miRNAs with stem-loop structure and 3′ overhangs. The pre-miRNAs are then exported from the nucleus into the cytoplasm by Exp 5 and further processed by another RNase III enzyme, Dicer, into miRNA duplexes. Finally, the miRNA duplex is unwound; one strand functions as the mature miRNA, which is incorporated into the RISC that contains Ago proteins at its core and other proteins including DEAD-box helicase protein DP103, gemin4, and MOV10. The miRNA-RISC complex binds specific sites in the 3′UTR of target mRNAs, disabling them through deadenylation, destabilization, and translational repression.

FIG. 2

A putative miRNA pathway for placental development and the pathogenesis of PE. During normal placentation, low levels of miR-17-family miRNAs (mir-17, miR-20a, and miR-20b) allow higher expression of EPHB4 and EFNB2 in the placenta. This facilitates the differentiation of CTB progenitors into invasive EVTs for invading the maternal decidua and for remodeling the uterine spiral arteries. The spiral arteries are transformed into low-resistance vessels with a much-reduced pressure, thereby causing blood flow to rise for facilitating the bidirectional mother-fetus exchanges of nutrients and respiratory gases (oxygen and carbon dioxide) and exclusion of fetal metabolic wastes. However, during abnormal placentation in PE, increased miR-17-family miRNAs suppress EFNB2/EPHB4 expression, further inhibiting endovascular transformation of CTBs and invasion of EVTs for spiral artery remodeling. Failed spiral artery remodeling constrains maternal-fetal interface blood flow, which contributes to the pathogenesis of PE.