Cignarella A. Selective agonists of estrogen receptor isoforms: new perspectives for cardiovascular disease. Arterioscler Thromb Vasc Biol

Abstract—The cloning of estrogen receptors (ERs) and generation of ER-deficient mice have increased our understanding of the molecular mechanisms underlying the cardiovascular effects of estrogen. It is conceivable that clinical trials of estrogens so far failed to improve cardiovascular health because of the poor ER isoform selectivity and tissue specificity of endogenous hormones as well as incorrect treatment timing and regimens. Tissue-selective ER modulators (SERMs) may be safer agents than endogenous estrogens for cardiovascular disease. Yet, designing isoform-selective ER ligands (I-SERMs) with agonist or antagonist activity is required to pursue improved pharmacological control of ERs, especially taking into account emerging evidence for the beneficial role of vascular ER activation. Ideally, the quest for unique ER ligands targeted to the vascular wall should lead to compounds that merge the pharmacological profiles of SERM and I-SERM agents. This review highlights the current bases for and approaches to selective ER modulation in the cardiovascular system. (Arterioscler Thromb Vasc Biol. 2006;26:000-000.) Key Words: estrogen receptor SERM selective ER ligands arterial wall vascular protection Coronary artery disease (CAD) accounts for one-third ofall deaths in postmenopausal women.1 A potential role for estrogen in cardiovascular disease (CVD) protection has been long suggested by the observations that women have a reduced relative CVD risk as compared with men, but thi