An epigenetic basis for maternal vascular adaptation to pregnancy

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 DESCRIPTION (provided by applicant): Cardiovascular disease is the number one cause of death in women, and pregnancy history is a major predictor of future cardiovascular health: Uncomplicated pregnancy is associated with diminshed risk of cardiovascular disease, and hyptertensive pregnancy is associated with a marked increased risk. At present, it is unknown whether pregnancy meerly identifies women with a high risk of future cardiovascular disese or whether pregancy actually alters future risk. Preliminary work by our group indicates that extensive remodeling of large conduit arteries (specifically the aorta) occurs during pregnancy and that this remodeling involves epigenetic changes in the vascular smooth muscle of the aorta. Based on these findings, we hypothesize that epigenetic modification is necessary for vascular adaptation and that any persistent effects of pregnancy on the aorta are accompanied by epigenetic changes. We propose to test this hypothesis through the following specific aims: 1) To determine whether global levels of DNA methylation and hydroxymethylation in the aorta reflect physiologic and morphologic changes that occur in pregnancy, and to assess the persistence of these epigenetic changes post partum. By systematically assessing epigenetic, physiologic, morphologic and gene expression parameters of the aorta of the laboratory mouse, we will test whether pregnancy related epigenetic DNA modifications indeed mirror other adaptive changes. 2) To test whether Tet gene down-regulation and concomitant epigenetic change is necessary for VSM phenotype switching and aortic adaptation during pregnancy. We will use lentivirus in order to force expression of Tet genes in VSM in the mouse, in order to directly test the hypothesis that aortic remodeling depends on Tet gene down-regulation. Relevance: The proposed studies are highly relevant to women's health, because they promise to shed light on a novel molecular mechanism through which pregnancy can have persistent effects on the mother's blood vessels and thereby impact her long-term risk of developing cardiovascular disease.