Emerging technologies offer new opportunities to explore effects of physiologic conditions associated with aging on gene expression. In women, many clinically relevant age-related diseases are associated with the loss of estrogen which occurs as a result of ovarian senescence and menopause. Coronary heart disease (CHD), the leading cause of death in both men and women, is infrequent in pre-menopausal women. However, in post-menopausal women the disease becomes increasingly prevalent such that CHD becomes the leading cause of death in women over 60. Estrogen replacement therapy has been shown to reduce the incidence of CHD in post-menopausal women, and to inhibit the progression of diet- induced atherosclerosis in ovariectomized animal models. Only a portion of the protective effect can be explained by alterations in traditional risk factors, and increasing evidence demonstrates that direct actions of estrogen on the artery are important in this protection. However, the cellular and molecular mechanisms of estrogen action on the artery are poorly defined. Estrogen receptors are present in vascular beds and cells, demonstrating the potential for estrogen to regulate vascular function through its specific receptors.Estrogen receptors may regulate gene expression through l) interactions with estrogen response elements in regulatory regions of target genes, or 2) interaction with other transcription factors, such as nuclear factor-kB (NF-kB), AP-1 (c-fos, c- jun), and PPAR-gamma. Thus, while there is potential for many genes to be regulated by estrogen, liftle is known regarding the range and depth of effects of estrogen on transcriptional events in vascular cells. Recently developed technologies allow the rapid and simultaneous screenin of the mRNA levels for many target molecules of known function and provide an excellent method for determination of the breadth of estrogen effects. The central hypothesis of the proposed studies is that estrogen inhibits the initiation and progression of atherogenesis in part through direct estrogen receptor-dependent effects on vascular gene expression. The specific aims are to determine the direct effects of estrogen on transcriptional events in vascular smooth muscle (VSMC) and endothelial cells (vEC) in order to gain insights into the progression of the disease as well as potential therapies to prevent this age-related disease.

R03AG018170

2000-09-30

2003-08-31