Characterizing the protective and deleterious vascular effects of estrogens

Abstract

Although estradiol (E2) appears to be a protection against early atheroma (fatty streak deposit), hormonal replacement therapy does not prevent cardiovascular events in post-menopausal women. We used transgenic models to dissect the mechanisms of complex pathophysiological processes such as atheroma, and to clarify the effect of endogenous hormones or drugs on this process. In the first part of this article, we briefly summarize the pathophysiology of atheroma, with a special emphasis on the recent advances obtained thanks to the use of transgenic mice. In the second part, we detail how the use of in vitro and mainly in vivo (transgenic mice) models helped to investigate the effects of estrogens on the normal and pathological arteries and the mechanisms mediating these effects. Briefly, endothelium appears to be an important target for estradiol (E2), because this hormone potentiates endothelial nitric oxide (NO) production, accelerates endothelial regrowth (thus favoring vascular healing) and prevents apoptosis of endothelial cells. The immuno-inflammatory system appears to play a key part in the development of fatty streak deposit as well as in the rupture of atherosclerotic plaque, and also represents major, but ambiguous, targets of estrogens. Finally, most of these effects of E2 are mediated by estrogen receptor α and are independent of estrogen receptor β. In summary, a better understanding of the mechanisms of estrogens on the normal and atheromatous arteries is required and should help to optimize the prevention of cardiovascular disease after menopause. Hence, the importance of mouse models to screen existing and future selective estrogen receptor modulators (SERMs) is discussed.