Journal
HYPERTENSION
Volume 61, Issue 4, Pages 864-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.111.203489
Keywords
ALK5; ALK7; miR-376c; Nodal; placenta; preeclampsia; TGF-beta
Categories
Funding
- Canadian Institute of Health Research [CIHR MOP-81370, CCI-92222]
- National Natural Sciences Foundation from China [81025004, 3081120430]
- Ontario Graduate Scholarship
- Ontario Women's Health Council/CIHR
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Preeclampsia is a major disorder of pregnancy and a leading cause of maternal and perinatal morbidity and mortality. MicroRNAs are small noncoding RNAs that regulate gene expression posttranscriptionally. In this study, we examined the expression of miR-376c and found that miR-376c levels were downregulated in both placental and plasma samples collected from preeclamptic patients, when compared with the normal pregnant women at the same gestational stage. Overexpression of miR-376c induced trophoblast cell proliferation, migration, and invasion in HTR8/SVneo cells and promoted placental explant outgrowth. In contrast, inhibition of endogenous miR-376c resulted in a decrease in trophoblast cell invasion and placental explant outgrowth. We identified activin receptor-like kinase 5 (ALK5), a type I receptor for transforming growth factor-beta, and ALK7, a type I receptor for Nodal, as targets of miR-376c. Overexpression of miR-376c repressed transforming growth factor-beta and Nodal functions, whereas overexpression of ALK5 and ALK7 reversed the effects of miR-376c. These results demonstrate that miR-376c inhibits both ALK5 and ALK7 expression to impair transforming growth factor-beta/Nodal signaling, leading to increases in cell proliferation and invasion. An unbalanced Nodal/transforming growth factor-beta and miR-376c expression may lead to the development of preeclampsia. (Hypertension. 2013;61:864-872.) circle Online Data Supplement
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