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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2192.)
© 2006 American Heart Association, Inc.

Brief Reviews

Selective Agonists of Estrogen Receptor Isoforms

New Perspectives for Cardiovascular Disease

Chiara Bolego; Elisabetta Vegeto; Christian Pinna; Adriana Maggi; Andrea Cignarella

From the Department of Pharmacological Sciences (C.B., E.V., C.P., A.M., A.C.), University of Milan; and Department of Pharmacology and Anaesthesiology (A.C.), University of Padova, Italy.

Correspondence to Prof Adriana Maggi, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, I-20133 Milan, Italy. E-mail adriana.maggi{at}unimi.it

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.

Despite a wealth of encouraging preclinical and epidemiological research, estrogenic hormones have not shown cardiovascular benefit in clinical trials. Based on molecular pharmacology studies, selective agonists of individual estrogen receptor isoforms targeted to the vessel wall represent a promising and safe strategy to bypass the limitations of endogenous hormones.

Key Words: estrogen receptor • SERM • selective ER ligands • arterial wall • vascular protection

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