Preeclampsia Is Associated with Alterations in DNA Methylation of Genes Involved in Collagen Metabolism

Maternal vascular dysfunction is a hallmark of preeclampsia. A recently described vascular phenotype of preeclampsia involves increased expression of matrix metalloproteinase-1 (MMP-1) in endothelial cells, vascular smooth muscle, and infiltrating neutrophils. In contrast, the expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) and collagen type Iα 1 is either reduced or not changed in the vessels, suggesting an imbalance in vessel collagen degradation and synthesis in preeclampsia. In the present study, we explored the possible contribution of DNA methylation to the altered expression of genes involved in collagen metabolism. We assayed the differences in DNA methylation in omental arteries from normal pregnant and preeclamptic women, and determined whether reduced DNA methylation increases the expression of MMP-1 in cultured vascular smooth muscle cells and a neutrophil-like cell line, HL-60. Several MMP genes, including MMP1 and MMP8, were significantly less methylated in preeclamptic omental arteries, whereas TIMP and COL genes either were significantly more methylated or had no significant change in their DNA methylation status compared with normal pregnancy. Experimentally induced DNA hypomethylation increased MMP-1 expression in cultured vascular smooth muscle cells and MMP-1 cells. Our findings suggest that epigenetic regulation contributes to the imbalance in genes involved in collagen metabolism in blood vessels of preeclamptic women.