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Review
. 2009 Jan;5(1):93-103.
doi: 10.2217/14796678.5.1.93.

Estrogen, aging and the cardiovascular system

James P Stice  1 , Jennifer S Lee, Angela S Pechenino, Anne A Knowlton
Affiliations
Review

Estrogen, aging and the cardiovascular system

James P Stice et al. Future Cardiol. 2009 Jan.

Abstract

Estrogen is a powerful hormone with pleiotropic effects. Estrogens have potent antioxidant effects and are able to reduce inflammation, induce vasorelaxation and alter gene expression in both the vasculature and the heart. Estrogen treatment of cultured cardiac myocytes and endothelial cells rapidly activates NFkappaB, induces heat-shock protein (HSP)-72, a potent intracellular protective protein, and protects cells from simulated ischemia. In in vivo models, estrogens protect against ischemia and trauma/hemorrhage. Estrogens may decrease the expression of soluble epoxide hydrolase, which has deleterious effects on the cardiovascular system through metabolism of epoxyeicosatrienoic acids. Natural (endogenous) estrogens in premenopausal women appear to protect against cardiovascular disease and yet controlled clinical trials have not indicated a benefit from estrogen replacement postmenopause. Much remains to be understood in regards to the many properties of this powerful hormone and how changes in this hormone interact with aging-associated changes. The unexpected negative results of trials of estrogen replacement postmenopause probably arise from our lack of understanding of the many effects of this hormone.

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Figures

Figure 1
Figure 1. Cardiovascular changes induced with ovariectomy in adult animal models
In the vasculature, ovariectomy (OVX) leads to increased vessel stiffness, ECM deposition, endothelial cell apoptosis, and sensitivity to vasocontrictive agents. OVX also leads to decreased expression and activity of eNOS and vasodilatory responses. In the myocardium, OVX decreases vascular tone, increases inflammation, myocardial stiffness, ECM deposition, apoptosis and can lead to LV hypertrophy. ECM: Extracellular matrix; eNOS: Endothelial nitric oxide synthase; LV: Left ventricular.
Figure 2
Figure 2. Changes in the endothelium and vascular smooth muscle in aged ovariectomized Norway Brown rats
NO is generated from L-arginine in the endothelium where it diffuses into the VSM and binds to the NO receptor, sGC. sGC converts GTP to cGMP, and activates a cascade of cGMP-dependant protein kinase and VASP. This results in a decrease in intracellular Ca2+ levels and vasorelaxation. Aged ovariectomy Norway Brown rats had no change in eNOS or NO, but decreased expression of sGC and decreased activation of VASP, leading to impaired relaxation in response to acetylcholine and sodium nitroprusside. E2 replacement attenuated these changes. eNOS: Endothelial NO synthase; NC: No change: NO: Nitric oxide; sGC: Soluble guanylyl cyclase; VASP: Vasodilator-stimulated phosphoprotein; VSM: Vascular smooth muscle.
Figure 3
Figure 3. Role of E2, epoxide hyrolase and NFκB in the cardiovascular system
17β-estradiol can increase vascular relaxation through the activation of eNOS and increased bioavailability of NO or upregulation of the NO receptor, soluble guanylyl cyclase. In addition, E2 suppresses ROS formation, which can decrease NO bio-availability through free-radical formation. NFκB activation induces heat-shock proteins, antiapoptotic proteins and inflammatory processes. While acute NFκB activation is protective, chronic activation leads to sustained inflammation and apoptosis. E2 is unique in that it acutely activates NFκB to protect cells from short-term stress, but long-term E2 treatment suppresses NFκB activation to protect cells from death. The expression of soluble epoxide hyrolase, which converts epoxyeico-satrienoic acids into dihydroxyeicosatrienoic acids, can potentially be inhibited by E2, thus allowing an additional mechanism to block long-term NFκB activation. E2: 17β-estradiol; EET: Epoxyeicosatrienoic acid; eNOS: Endothelial NO synthase; DHET: Dihydroxyeicosatrienoic acid; ROS: Reactive oxygen species; sEH: Epoxide hydrolase; NO: Nitric oxide.
Figure 4
Figure 4. Altered vascular responsiveness to hormone therapy with age
The efficacy and effect of HT changes based on the stage of atherosclerotic disease and timing HT is initiated. As the disease state of atherosclerosis progresses the beneficial effects of early HT (increased vasodilation and decreased inflammatory activation and lesion progression) are replaced by more deleterious delayed HT effects. In the setting of advanced atherosclerotic disease, estrogens are less effective due to decreased estrogen-receptor expression and function, which leads to decreased vasodilation, increased inflammation and plaque instability. The roles that other steroid receptors and coregulators in the vasculature play in nuclear receptor signaling are less understood. HT: Hormone therapy; LXR: Liver X receptor; PPAR: Peroxisome proliferator-activated receptors Reproduced with permission from [75], © The Endocrine Society (2008).
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