Vascular actions of estrogens: functional implications

Abstract

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.

Figure 1

Schematic of the current hypothesis concerning the impact of estrogen treatment on mitochondrial function. Estrogen appears to promote energy production (oxidative phosphorylation) while decreasing mitochondrial generation of reactive oxygen species (ROS). The oxidative phosphorylation system is composed of five enzyme complexes, within the inner mitochondrial membrane. Activity of this system generates an electrochemical gradient across this membrane which leads to production of ATP. At the same time, electrons leaking into the mitochondrial matrix interact with oxygen, resulting in superoxide production. Superoxide is then metabolized by Mn superoxide dismutase (MnSOD); the resulting H₂O₂ is reduced to water by glutathione peroxidase-1 (GPx1). H₂O₂ can also be converted by the Fenton reaction to the highly reactive hydroxyl radical (OH·). ROS in the mitochondrial matrix target lipids, proteins and mtDNA. Adapted from (Duckles et al., 2006).

Figure 2

Schematic of metabolic pathways involved in the synthesis and biotransformation of estrogen in the liver and extravascular tissue. Estrogen and some metabolites each have specific binding affinities for estrogen receptors. In addition, other metabolites of estrogen also have biological activities that do not require binding to the classically defined receptors. Identification of differences in copy numbers of genes and polymorphisms in CYP enzymes will affect the efficacy of a particular estrogenic treatment as well as impact the biological consequence of that treatment depending upon the rate of metabolism and the end product (see Table 2). Competition of the catechol estrogens with adrenergic transmitters for catechol O-methyltransferase (COMT) will affect the rate at which adrenergic neuronal signaling is sustained. Abbreviations: CYP, cytochrome P450 enzymes designated by numbers; HSD17B1, 17 β-hydroxysteroid dehydrogenase; SuLT, sulfatases; SULTs, sulfotransferases. Modified from Figure 4 of (Miller and Mulvagh, , 2007).