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Published online before print June 25, 2008

0031-6997/08/6002-210-241$7.00
Pharmacol Rev 60:210-241, 2008

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Vascular Actions of Estrogens: Functional Implications

Virginia M. Miller and Sue P. Duckles

Surgery and Physiology, Mayo Clinic College of Medicine, Rochester, Minnesota (V.M.M.); and Pharmacology, University of California, Irvine, School of Medicine, Irvine, California (S.P.D.)

Abstract
I. Introduction
II. Estrogen Synthesis and Receptors
    A. Estrogenic/Androgenic Balance
    B. Receptors for Estrogen
        1. Ligand-Activated Transcription Factors.
        2. G Protein-Coupled Estrogen Receptor.
III. General Mechanisms of Action
    A. Effects on Gene Transcription
    B. Rapid Effects
    C. Post-Transcriptional and Translational Modulation of Proteins/Enzymes
        1. RNA Stability.
        2. Post-Translational Modification of Proteins.
IV. Mitochondria
V. Physiological Consequences
    A. Vascular Responsiveness
        1. Arteries.
        2. Veins.
    B. Angiogenesis
    C. Vascular Consequences of Estrogenic Modulation of Autonomic Function
        1. Hypertension, Sympathetic Tone, and Stress.
        2. Metabolism of Adrenergic Neurotransmitter and Regulation of Adrenergic Receptors.
        3. Variation in Vasomotor and Neuronally Mediated Symptoms of Menopause—Genetic Considerations.
VI. Estrogenic Effects in Pathophysiology
    A. Inflammation
    B. Atherosclerosis
        1. Peripheral Arterial Disease.
        2. Carotid Intimal Medial Thickness.
        3. Coronary Arterial Calcification.
        4. Endothelial Dysfunction and Other Modalities to Assess Cardiovascular Risk in Menopausal Women.
    C. Stroke
    D. Migraine
    E. Thrombosis
VII. Future Directions: Summary
    A. Pharmacogenomics
    B. Variation of Physiological/Pathological Impact of Hormones across the Lifespan
The impact of estrogen exposure in preventing or treating cardiovascular disease is controversial. But it is clear that estrogen has important effects on vascular physiology and pathophysiology, with potential therapeutic implications. Therefore, the goal of this review is to summarize, using an integrated approach, current knowledge of the vascular effects of estrogen, both in humans and in experimental animals. Aspects of estrogen synthesis and receptors, as well as general mechanisms of estrogenic action are reviewed with an emphasis on issues particularly relevant to the vascular system. Recent understanding of the impact of estrogen on mitochondrial function suggests that the longer lifespan of women compared with men may depend in part on the ability of estrogen to decrease production of reactive oxygen species in mitochondria. Mechanisms by which estrogen increases endothelial vasodilator function, promotes angiogenesis, and modulates autonomic function are summarized. Key aspects of the relevant pathophysiology of inflammation, atherosclerosis, stroke, migraine, and thrombosis are reviewed concerning current knowledge of estrogenic effects. A number of emerging concepts are addressed throughout. These include the importance of estrogenic formulation and route of administration and the impact of genetic polymorphisms, either in estrogen receptors or in enzymes responsible for estrogen metabolism, on responsiveness to hormone treatment. The importance of local metabolism of estrogenic precursors and the impact of timing for initiation of treatment and its duration are also considered. Although consensus opinions are emphasized, controversial views are presented to stimulate future research.

Address correspondence to: Dr. Virginia M. Miller, Professor, Surgery and Physiology, Mayo Clinic College of Medicine, Rochester, MN 55905. E-mail: miller.virginia{at}mayo.edu






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