OESTROGEN AND VASCULOPROTECTION

The lower incidence of atherosclerosis in premenopausal women compared with men has attracted considerable attention to the possible cardiovascular protective actions of oestrogen. Although the anti-atherosclerotic actions of oestrogen were originally thought to arise from an action on lipids, it is now clear that oestrogen exerts beneficial actions directly on the vasculature, generally through an action on specific receptors. Oestrogen receptors (ER) are members of the steroid/thyroid hormone receptor superfamily of ligandactivated transcription factors. There are two receptors that have been identified for oestrogen, ERa and ERb, each of which have been found in both smooth muscle and endothelial cells and may be important in the ability of oestrogen to reduce cellular proliferation. In the vasculature, oestrogen is protective through the promotion of the replacement of damaged endothelium, inhibition of proliferation of vascular smooth muscle cells and the reduction of extracellular matrix formation, as well as vasodilatation. The role of the individual ER subtypes in vasculoprotection remains controversial. It has been reported that ERa promotes re-endothelialization, inhibits smooth muscle cell proliferation and reduces the progression of atherosclerotic plaque; ERb has also been reported to reduce proliferation of vascular smooth muscle and to reduce neointima formation. However, Geraldes et al. reported that ERa selectively mediated the effects of oestrogen on endothelial cells, whereas ERb only mediated the inhibition of smooth muscle proliferation. In contrast, Pare et al., using ER-knockout mice, concluded that ERa rather than ERb mediated the vasculoprotective actions of oestrogen. In this issue of the journal, Odenlund et al. use a coculture system of endothelial and vascular smooth muscle cells to address the mechanism of the antiproliferative effects of oestrogen. The cells are shown to express both ERa and ERb, but the role of the receptors in the actions of oestrogen has not been addressed in this study. Clearly, the roles of the ER subtypes in the vasculoprotective actions of oestrogen remain unclear and need further investigation. The most significant finding in the report of Odenlund et al. is that the effects of oestradiol on proliferation of vascular smooth muscle cells (VSMC) in response to fetal calf serum involves an interaction between VSMC and endothelial cells (EC), because there was no effect on either VSMC or EC when cultured alone. In contrast, when cells were cocultured, oestradiol exerted a significant antiproliferative action. Although the minimal effect on VSMC alone is consistent with previous reports of limited antiproliferative activity on cells from rats, other studies using VSMC derived from human tissue report more substantial antiproliferative responses to oestrogens in the absence of endothelial cells. This does raise the question as to whether oestrogen may exert an even greater effect on human VSMC if they are cultured with EC. It is well established that oestrogen increases the production and release of endotheliumderived nitric oxide (NO), involving both ER-mediated gene transcription and rapid intracellular signalling (i.e. genomic and non-genomic effects). With longer-term treatment, oestrogen can increase endothelial nitric oxide synthase (eNOS) activity associated with an increased expression of calmodulin, which promotes eNOS activity and a decreased expression of caveolin, which inhibits eNOS activity. Acutely, oestradiol increases eNOS phosphorylation at Ser to enhance endothelium-dependent relaxation. Somewhat surprisingly, the antiproliferative actions of oestradiol reported by Odenlund et al. do not appear to involve NO, although it would have been useful to know whether oestradiol increased NO synthesis in the coculture system used in that study. The report from Odenlund et al. suggests that an interaction between VSMC and EC may be important in the vasculoprotective actions of oestrogen, which should be considered in further investigations of the antiproliferative actions of oestrogen.