Testosterone attenuates expression of vascular cell adhesion molecule-1 by conversion to estradiol by aromatase in endothelial cells: Implications in atherosclerosis

Abstract

We previously reported that testosterone attenuated atherogenesis in LDLR ؊͞؊ male mice, and that this effect of testosterone was most likely caused by its conversion to estradiol. Estradiol inhibits vascular cell adhesion molecule-1 (VCAM-1) expression, and expression of VCAM-1 is one of the early events in atherogenesis. We assessed the cellular mechanism(s) involved by which testosterone attenuates atherogenesis. We evaluated whether testosterone inhibited TNF␣-induced VCAM-1 expression via its conversion to estradiol by the enzyme aromatase in human umbilical vein endothelial cells (HUVEC). Aromatase mRNA was dedected by reverse transcription-PCR in these cells. Testosterone (30 nM-1 M) attenuated VCAM-1 mRNA expression in a concentration-dependent manner. The non aromatizable androgen, dihydrotestosterone, had no effect on VCAM-1 mRNA expression. Testosterone was less effective in attenuating VCAM-1 expression in the presence of anastrozole, an inhibitor of aromatase, indicating that testosterone inhibited VCAM-1 via conversion to estradiol. Estradiol also attenuated VCAM-1 mRNA expression, but this action was not abolished in the presence of anastrozole, indicating that anastrozole itself did not modulate VCAM-1 mRNA expression. The effect of testosterone on VCAM-1 mRNA expression was inhibited in the presence of the estrogen receptor antagonist, ICI-182780. Testosterone also attenuated TNF␣-induced VCAM-1 protein expression, and this attenuation was abolished in the presence of anastrozole. In conclusion, testosterone inhibited VCAM-1 mRNA and protein expression in HUVEC by its conversion to estradiol via the enzyme aromatase present in the endothelial cells. Results from our study may help explain the mechanism by which testosterone may have beneficial effects on the cardiovascular system. atherosclerosisat ͉ sex steroids ͉ androgens

Regulation of adrenomedullin release from human endothelial cells by sex steroids and angiotensin-II

“…The latter possibility is supported by investigations of other vascular systems, including prostacyclin production in endothelial cells (Mikkola et al 1995) and AT1 receptor gene expression in smooth muscle cells (Nickenig et al 1998), which have revealed that oestradiol may have a maximum effect at 12 h or greater. Endothelial cells can convert testosterone to oestradiol (Mukherjee et al 2002) and it has been suggested that effects attributed to testosterone may be in part a result of its conversion to oestradiol (Sierra-Ramirez et al 2004). However, our observation that testosterone increased the number of adrenomedullin-secreting endothelial cells, and that oestradiol had no significant effect, indicates that the actions of testosterone exhibited here were unlikely to be dependent on its conversion to oestradiol.…”

Free testosterone plasma levels are negatively associated with the intima-media thickness of the common carotid artery in overweight and obese glucose-tolerant young adult men

“…32 This phenomenon may help explain the mechanism by which testosterone may have beneficial effects on the cardiovascular system; however, this effect is mediated by endothelial cell aromatase, converting testosterone to estradiol. 32 IMT-CCA has been shown to be associated with the prevalence of cardiovascular disease 33 and atherosclerotic involvement of other arterial beds, including the coronary arteries, 11,12 and to represent a strong predictor of both myocardial infarction and stroke, 13 even in subjects with no history of cardiovascular disease. 9 Therefore, the results from this study based on IMT-CCA measurements in overweight and obese men may be potentially extrapolated to suggest that hypotesteronemia enhances the susceptibility to atherosclerosis in multiple arterial districts and increases the risk for CHD.…”

Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor

“…Indeed, female sex and estrogens appear to be protective against a range of inflammatory diseases including multiple sclerosis and Alzheimer's to atherosclerosis (Nilsson 2007). Similarly, estrogens appear to suppress the inflammatory responses in experimental models of inflammation in both in vivo and in vitro systems (Nathan et al 1999, Mukherjee et al 2002, Card et al 2006. A significant proportion of this antiinflammatory activity has been attributed to alterations in NO synthesis and activity (Thompson & Khalil 2003, Orshal & Khalil 2004; however, EDHF has also been proposed to play a role.…”

“…In addition, there is some evidence suggesting that male sex hormones exert inhibitory effects on leukocyte recruitment. Indeed, testosterone inhibits VCAM-1 mRNA and protein expression in HUVECs, although this action is dependent upon conversion to 17b-estradiol via aromatase activity, an enzyme present in endothelial cells (Mukherjee et al 2002). There is also evidence to suggest that rather than directly affecting adhesion molecule expression, estrogens suppress the expression of specific chemokines (chemoattractant cytokines) that are produced by endothelial cells among other cell types.…”