Estrogen inhibits cuff-induced intimal thickening of rat femoral artery: effects on migration and proliferation of vascular smooth muscle cells
Introduction
It is an established epidemiological observation that the incidence of atherosclerosis is lower in premenopausal women than in men and increases after menopause 1, 2. Estrogen replacement therapy is effective to protect women from coronary heart disease 2, 3, 4. Estrogen has also been reported to inhibit the development of atherosclerosis in animal experiments 5, 6, 7. These epidemiological and experimental findings suggest that estrogen has an anti-atherogenic action. The mechanism, however, is not fully understood.
A number of investigators have reported that lipid metabolism is improved by estrogen administration 5, 6, 8, 9, 10. Estrogen increases serum high-density lipoprotein cholesterol level and decreases serum low-density lipoprotein cholesterol level. On the other hand, the existence of functional estrogen receptors in vascular endothelial cells [11]and vascular smooth muscle cells (VSMCs) 12, 13, 14suggests that estrogen acts directly on the arterial wall. Estrogen appears to have both endothelium-independent 15, 16and endothelium-dependent 17, 18, 19vasodilator actions. A calcium-antagonistic effect 15, 16, regulation of prostacyclin 20, 21and nitric oxide production [22]may be involved in these effects.
Migration and proliferation of VSMCs are fundamental steps in the development of atherosclerosis [23]and neointimal formation after endothelial injury [24]. However, the effect of estrogen on migration of cultured VSMCs is not known. Moreover, the effect of estrogen on proliferation of VSMCs is controversial. Fischer-Dzoga et al. [25]and Vargas et al. [26]reported an inhibitory effect of estrogen on VSMC proliferation, while Farhat et al. [27]demonstrated a stimulatory effect of estrogen.
We first aimed at investigating the effect of estrogen on cuff-induced intimal thickening of the rat femoral artery. The reason we used this model was that lipid metabolism was not involved in the development of intimal thickening by cuff placement. We further examined the effect of estrogen on migration and proliferation of cultured VSMCs to investigate the mechanism underlying the effect on intimal thickening.
Section snippets
Chemicals
Estradiol dipropionate was obtained from Teikoku Hormone (Tokyo, Japan). Dulbecco's modified Eagle's medium (DMEM) was purchased from GIBCO BRL (Gaithersburg, MD) and fetal bovine serum (FBS) from ICN Biomedicals (Osaka, Japan). Bovine serum albumin (BSA), trichloroacetic acid (TCA) and Triton X-100 were purchased from Wako (Osaka, Japan). Phenol red-free DMEM, 17β-estradiol (E2), 17α-estradiol, progesterone, testosterone, endothelin-1, human basic fibroblast growth factor (bFGF), indomethacin,
Sex-related difference in intimal thickening
Cuff placement induced diffuse intimal thickening of the rat femoral artery, while no intimal thickening was observed in the control rats without cuff placement. We checked the time-related change in the development of intimal thickening. The I:M ratio was significantly higher 2 weeks after than 1 week after cuff placement (P<0.05) and then tended to decrease until 4 weeks after cuff placement: 1 week, 0.11±0.01 (n=8); 2 weeks, 0.33±0.07 (n=9); 3 weeks, 0.25±0.05 (n=8); 4 weeks, 0.21±0.02 (n
Discussion
In the present study, we showed that intimal thickening of the rat femoral artery induced by cuff placement was greater in males than that in control females. Intimal thickening of females was increased by ovariectomy and this increase was reversed by estrogen replacement.
Arterial intimal thickening induced by a polyethylene cuff has been reported in the rabbit femoral artery [38]and in the rabbit carotid artery [28]. Histological observations in these studies elucidate that cuff placement
Acknowledgements
We would like to thank Masae Watanabe and Hitomi Yamaguchi for their excellent technical assistance. This work was supported by grants from the Uehara Memorial Foundation and the Sankyo Life Science Research Foundation. This work was presented in part at the 10th International Symposium on Atherosclerosis in Montréal, October 9–14, 1994.
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2018, Vascular PharmacologyCitation Excerpt :Overwhelming evidence clearly shows that the effect of estrogen on VSMCs is largely affected by the site from where they were isolated. For instance, 17β-estradiol inhibited neointimal hyperplasia, characterized by increased proliferation and migration of VSMCs, in the femoral artery of rats and mice [37,38], the aorta and iliac artery of rabbits [39], as well as the carotid artery of mice, rats and pigs [40–44]. Using estrogen receptor knockout mice, Pare et al. attributed these effects to ERα receptor [44].
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2012, Biochemical and Biophysical Research CommunicationsCitation Excerpt :In animal models of vascular injury, administration of E2 is reported to have vasoprotective effects and can alleviate the development of intimal hyperplasia [11–13]. However, in vitro data are contentious; whilst most studies concur that E2 inhibits SMC proliferation and migration [11–14], some claim that E2 augments SMC proliferation [15,16]. The applicability of these variable outcomes to human macrovasculature is not clear, hence the use of clinically relevant tissues and cells to study etiology of cardiovascular disease is important in this regard.
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2012, Journal of CardiologyCitation Excerpt :Our research demonstrated that older women have more severe cardiac failure and multivessel disease at admission. Estrogen would be a probable candidate for the physiological differences between men and women, since many reports have suggested a protective effect of estrogen on vascular smooth muscle and the heart [28–31]. The influence of sex hormones on cardiac events is also suggested by the report that androgens influence the QT interval [32].