There is now strong epidemiological evidence that estrogen replacement therapy has a protective effect in postmenopausal women. The cardiovascular protective action of estrogen is reported to be mediated indirectly by an effect on lipoprotein metabolism and by a direct effect on the vessel wall itself. Estrogen is active both in vascular smooth muscle and endothelium. Functionally competent estrogen receptors have been identified in vascular smooth muscle cells, and specific binding sites have been demonstrated in endothelium. Estrogen administration promotes vasodilation both in human and experimental animals, in part by stimulating] prostacyclin and nitric oxide synthesis. Both the prostaglandin synthase and the constitutive nitric oxide synthase were recently reported to be induced by estrogen treatment. In vitro, estrogen exerts a direct inhibitory effect on the smooth muscle by inhibiting calcium influx. In addition, estrogen inhibits vascular smooth muscle cell proliferation. In vivo, estradiol-17 beta prevents neointimal thickening after balloon injury and in rabbit cardiac transplant allografts. These data are consistent with in vitro studies wherein estrogen inhibits [3H]thymidine uptake by arterial segments from porcine coronary artery as well as proliferation of rabbit aortic vascular smooth muscle cells induced by hyperlipedemic serum. Recent studies have also reported an effect of estrogen on directed vascular smooth muscle cell migration. Furthermore, like other steroids, the effect of estrogen on the vessel wall has a rapid nongenomic component involving membrane phenomena, such as alteration of membrane ionic permeability and activation of membrane-bound enzymes, as well as the classical genomic effect involving estrogen receptor activation and gene expression. The nature of these estrogen response genes in the vessel wall and their relation to vasodilation and antiproliferation remain to be determined.

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1 The effect of oestradiol 17p on vascular smooth muscle proliferation was examined in segments of the pig left anterior descending coronary artery (LAD). It was established by cytochemical techniques that out-growth from the segments was composed of vascular smooth muscle cells. 2 [3H]-thymidine uptake by pig LAD segments was used as an index of vascular smooth muscle cell proliferation. Nitroprusside and forskolin significantly inhibited [3H]-thymidine uptake and were used as positive controls. 3 Oestradiol 171 (180 -360 nM) inhibited thymidine uptake by pig LAD segments (P <0.05). The inhibition was observed only in the absence of phenol red, which is a weak oestrogen receptor agonist. The anti-oestrogens tamoxifen and its more potent metabolite 4-hydroxytamoxifen, both of which are partial oestrogen receptor agonists, also significantly inhibited thymidine uptake. However, pretreatment with either tamoxifen or 4-hydroxytamoxifen did not signficantly block oestradiol 17p-induced inhibition of thymidine uptake. 5 The data suggest that oestradiol 171 inhibits smooth muscle cell proliferation in porcine LAD segments, possibly through an oestrogen receptor mechanism. This in vitro effect suggests an in vivo role for oestradiol 171 in directly protecting coronary arteries against myointimal proliferation in premenopausal women.

1 We studied the effects of oestradiol 17p on the development of pulmonary vascular changes and right ventricular (RV) hypertrophy in response to monocrotaline in male Sprague-Dawley rats.2 Rats were treated with either placebo or oestradiol 17p (1O mg) in the form of slow release pellets implanted subcutaneously 48 h before monocrotaline administration. Rats were injected with either saline or a single dose of monocrotaline (60 mg kg-', i.m.). Pulmonary vascular changes and RV hypertrophy were studied at 4 weeks following monocrotaline administration. 3 Monocrotaline induced a significant increase in the ratio of right ventricle (RV) to left ventricle-plusseptum (LV + S) weights. Monocrotaline-treated rats also showed significant myointimal proliferation in small pulmonary arteries, decrease of arterial numbers and increase in the number of abnormal alveolar macrophages.4 Oestradiol 17p attenuated myointimal hyperplasia in pulmonary vessels, decreased the RV/(LV + S) ratio in monocrotaline-treated rats. Oestradiol 1713 had no significant effect on control animals. 5 Oestradiol treatment prevented the increase in lung wet to dry weight ratio, observed 7 days post monocrotaline administration.6 These results suggest that oestradiol 17p protects against the pulmonary vascular remodelling and RV hypertrophy associated with monocrotaline-induced pulmonary hypertension in the rat. Oestradiol also protects against microvascular leak observed in the early days of lesion.

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