Elsevier

Vascular Pharmacology

Volume 38, Issue 2, February 2002, Pages 89-98
Vascular Pharmacology

Effect of estrogen on endothelial function and angiogenesis

https://doi.org/10.1016/S0306-3623(02)00131-3Get rights and content

Abstract

Animal studies evaluating gender difference, the effects of gonadectomy and estrogen replacement and clinical studies in post-menopausal women with and without estrogen replacement therapy (ERT) proved that estrogen exerts significant benefits on the cardiovascular system. Since effects on the plasma lipoprotein profile is responsible for only ∼25–40% of the cardiovascular protection exerted by estrogens, it is postulated that direct effects of estrogen on the vascular wall must play an important role. Indeed, experimental and clinical evidence accumulated over the past decade, and reviewed briefly here, indicate that at least a part of cardiovascular benefits of 17β-estradiol can be attributed to the direct effect of the ovarian sex steroid hormone on vascular endothelial cells. Maintenance and upregulation of endothelial nitric oxide production and suppression of EDCF generation by 17β-estradiol may play an important role in preventing or reversing endothelial dysfunction, associated with atherosclerosis, hypertension and other cardiovascular diseases. Stimulation of angiogenesis (especially collateral vessel formation in ischemic tissues) by the ovarian steroid hormone could be beneficial in coronary artery disease, peripheral vascular disease, cerebral ischemia (stroke) and congestive heart failure. Despite these indisputable beneficial effects, several key questions remain to be answered in the future, including the better understanding of the apparently opposite effects of estrogen on prevention of cardiovascular disease vs. treatment of existing disease.

Introduction

Animal studies evaluating gender difference, the effects of gonadectomy and estrogen replacement and clinical studies in postmenopausal women with and without estrogen replacement therapy (ERT) collectively proved that estrogen exerts significant benefits on the cardiovascular system (Rubanyi and Kaufmann, 1998). Epidemiological data showed that ERT in postmenopausal women reduces the morbidity and mortality associated with cardiovascular diseases by ∼50% Stampfer et al., 1991, Isles et al., 1992, Farhat et al., 1996, Kauser and Rubanyi, 1997a. The exact mechanism of cardiovascular protection by estrogen is not known. Beneficial effects on the plasma lipoprotein profile are responsible for only ∼25–40% of the protection. It is postulated that direct effects of estrogen on the vascular wall (primarily on endothelial cells) must play an important role. Nitric oxide (NO), produced by the endothelial constitutive nitric oxide synthase enzyme (NOS-III), seems to be an ideal mediator of the beneficial cardiovascular effects of 17β-estradiol due to its multiple vasculoprotective actions. Facilitating angiogenesis and collateral vessel formation may also contribute to the beneficial effects of estrogen on the cardiovascular system Rubanyi et al., 1997a, Rubanyi et al., 1997b. Most of the data in the literature describe the benefits of estrogen in preventing morbidity and mortality due to cardiovascular diseases. However, some of the known biological actions of the ovarian steroid hormone (e.g., induction of proinflammatory cytokines (Winkler and Jackson, 2000), and vascular adhesion molecules Cid et al., 1994, Frazier-Jessen and Kovacs, 1995) may counteract its beneficial effects. Indeed, two recent clinical studies in postmenopausal women with established coronary artery disease showed that estrogen replacement (at least in the short term) accelerated, rather than inhibited, disease progression Heckbert et al., 2001, Alexander et al., 2001. In this paper, we give a brief overview of experimental and clinical evidence (along with new unpublished observations from our laboratory) supporting the role of 17β-estradiol in the modulation of endothelium-dependent vascular tone regulation and angiogenesis.

Section snippets

Modulation of endothelium-dependent vascular tone regulation

The endothelium plays an important role in modulating the tone of the underlying vascular smooth muscle by the synthesis and release of both vasodilator (e.g., NO, prostacyclin, endothelium-derived hyperpolarizing factor) and vasoconstrictor factors (EDCF) (e.g., PGH2, endothelin, oxygen-derived free radicals) Rubanyi and Ryan, 1991, Rubanyi, 1992, Rubanyi and Vanhoutte, 1990. Estrogen was shown to be modulating the synthesis/release of both vasodilator (especially NO) and vasoconstrictor

Angiogenesis related to ovulation and pregnancy

The majority of angiogenesis seen in mammals occurs during embryogenesis (Rissau and Flamme, 1995). The adult animal demonstrates a down-regulation of angiogenic responses compared to developing embryos under normal, nonpathological, conditions. The exceptions to this generalization are found in females where during the maturation of the ovarian follicle Koos and Le Maire, 1983, Modlich et al., 1996, the priming of the endometrium for implantation Findlay, 1986, Reynolds et al., 1992 and during

Conclusions and future perspectives

Experimental and clinical evidences accumulated over the past decade, and reviewed briefly here, indicate that at least a part of cardiovascular benefits of 17β-estradiol can be attributed to the direct effect of the ovarian sex steroid hormone on vascular endothelial cells. Maintenance and up-regulation of EDNO production and suppression of EDCF generation by 17β-estradiol may play an important role in preventing or reversing endothelial dysfunction, associated with atherosclerosis,

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