Earlier studies of the ADM gene promoter have revealed that, in addition to two transcription factors, nuclear factor for interleukin-6 expression (NF-IL6) and activator protein 2 (AP-2), the ADM gene expression is regulated by the hypoxia inducible factor-1 (HIF-1). Under hypoxia conditions, HIF-1 binds to the hypoxia response elements (HRE) in the ADM gene promoter to promote ADM gene expression. Although outside the focus of the present study, we have also detected putative HRE sequences in the intermedin gene promoter and demonstrated that hypoxia conditions stimulate intermedin gene promoter activity, suggesting that HIF-1 could play a role in the regulation of intermedin gene expression. Unlike intermedin, the expression of CGRP and ADM is not actively stimulated by estrogens, suggesting that these two related peptides are not directly associated with the cardiovascular effects of estrogens. In females, 17β-estradiol produced by ovaries is the chief circulating estrogen which increases vasodilatation and inhibits the response of blood vessels to injury. Studies by Mercuro et al. have shown that surgical-induced menopause causes an increase in peripheral vascular resistance and blood pressure. Likewise, a cross sectional study showed that there is a four- fold increase in the incidence of hypertension in postmenopausal women as compared to premenopausal individuals (40% in post menopausal women vs 10% in premenopausal women). The rise in systolic blood pressure per decade was around 5mmHg greater in perimenopausal and postmenopausal women as compared with premenopausal women . In addition to demographic studies, studies have shown that estrogen could dilate coronary and brachial arteries in postmenopausal women. A part of vasodilatation and hypotensive activities of 17β-estradiol could be explained by its ability to modulate the expression of genes known to influence vascular tone and structure, such as ACE, rennin, and angiotension type I (AT1) receptors. However, none of these genes have been shown to be specific direct targets for estrogen receptors and are responsible for the vasoprotective effects of estrogens. Based on our findings that intermedin is a hypotensive factor and contains putative ERE sequence in the promoter region, we propose that intermedin is a pituitary-derived blood pressure modulating factor directly regulated by ovarian estrogens. Based on this understanding, we further hypothesize that the down regulation of intermedin in aging individuals with estrogen deficiency could be responsible for postmenopausal hypertension. Because there is no established animal model suitable for the study of naturally occurring menopause, we will test our hypothesis by studying the relationship between plasma intermedin concentration and blood pressure among women in difference reproductive stages.