Sex Steroids Block the Initiation of Atherosclerosis

Abstract

Atherosclerosis is the main cause of death in men and women. This so-called ''hardening of the arteries'' results from advanced atherogenesis, the accumulation and death of subendothelial fat-laden macrophages (vascular plaque). The macrophages are attracted as the result of signals from injured vessels recruiting and activating cells to quell the injury by inflammation. Among the recruited cells are circulating monocytes that may be captured by the formation of neural cell adhesion molecule (nCAM) tethers between the monocytes and vascular endothelium; the tethers are dependent on electrostatic binding between distal segments of apposed nCAM molecules. The capture of monocytes is followed by their entry into the subendothelial area as macrophages, many of which will remain and become the fat-laden foam cells in vascular plaque. Neural cell adhesion molecules are subject to sialylation that blocks their electrostatic binding. We showed that estradiol-induced nCAM sialylases are present in vascular endothelial cells and tested whether sex steroid pretreatment of human vascular endothelium could inhibit the capture of monocytes. Using in vitro techniques, pretreatment of human arterial endothelial cells with estradiol, testosterone, dehydroepiandrosterone and dihydrotestosterone all induced sialylation of endothelial cells and, in a dose-response manner, reduced the capture of monocytes. Steroid hormones are protective against atherogenesis and its sequellae. Sex steroid depletion is associated with atherosclerosis. Based on this knowledge plus our results using sex steroid pretreatment of endothelial cells, we propose that the blockade of the initial step in atherogenesis by sex steroid-induced nCAM sialylation may be crucial to hormonal prevention of atherosclerosis.Keywords sex hormones, atherogenesis, prevention, neural cell adhesion molecule, estradiol, cardioprotection, menopause Cardiovascular disease (CVD) is the leading cause of death in both sexes. Among American women, 30% to 40% die of CVD or its complications. Prior to the onset of menopause, women have a lower incidence of CVD than men; symptomatic CVD (angina and infarction) appear about a decade earlier in men than women. 1 After menopause, at which time women become estrogen depleted, the CVD rates become similar to those of men.2 Additionally, women with premature menopause or premature ovarian failure who are not treated with estrogen have a well-documented increased rate of CVD and CVD-related death. [3][4][5][6][7][8] Since coronary events usually follow the cessation of ovarian function in women, it has long been supposed that sex steroids, particularly estrogen, are cardioprotective, and that approximately 10 years were needed to develop clinical disease. 9 Observational studies support this conclusion, and we know menopausal women who are treated with hormone replacement therapy within the first several years of menopause onset showed improvement in cardiovascular markers of disease.3,10-16 Age-adjusted subanalysis and long-term fol...

The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned?

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“…It has been demonstrated that activation of ERs by estradiol inhibits LPS-induced CD11b-expression [32]. Indeed, estradiol blunts monocytes adhesion to EC through a rapid signaling pathway mediated by a subset of ER located at cell membrane [33].Moreover, recent evidence in the literature showed that sex steroids blocks the initiation of atherosclerosis through the sialylation of EC-CAMs and consequently prevents the capture of monocytes [34].…”

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“…Estradiol has also been shown to inhibit monocyte adhesion to vascular endothelium, a known step in the development of atheromas and arteriosclerosis 19 . Evidence now suggests that this process is mediated by sex steroid–induced inhibition (more specifically, sialylation) of neural cell adhesion molecules (nCAMs), which are among the early arresting mechanisms for capturing leukocytes in areas of inflammation; sex steroid–induced sialylation of nCAM molecules prevented attachment of monocytes to endothelial cells 20 . Similar effects on leukocyte capture by hormonal manipulation, but not directly related to cardioprotection have been published 21, 22 .…”

“…For the sake of brevity, the normal course of plaque development is shown in Figure 2 53 . Monocytes are captured by inflamed vascular endothelial cells in part via tethers of nCAM:nCAM molecules expressed by monocytes and endothelial cells 20 . Coronary vessel endothelial cells express aromatase and estrogen receptors 13 .…”