title: Preeclampsia is associated with alterations in DNA methylation of genes involved in collagen metabolism.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia 23298-0034, USA.
authors.forename: Ahmad A
authors.initials: AA
authors.lastname: Mousa
authors.forename: Renato E
authors.initials: RE
authors.lastname: Cappello
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Estrada-Gutierrez
authors.forename: Juhi
authors.initials: J
authors.lastname: Shukla
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Strauss
authors.forename: Scott W
authors.initials: SW
authors.lastname: Walsh
mesh_terms: D000328:Adult; D001374:Azacitidine / Q000494:pharmacology; D001808:Blood Vessels / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics* / Q000378:metabolism*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011225:Pre-Eclampsia / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D019714:Tissue Inhibitor of Metalloproteinases; D003094:Collagen; D020782:Matrix Metalloproteinases; D001374:Azacitidine; D013755:Tetradecanoylphorbol Acetate