Skip to main content
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1993 Jul;109(3):612–617. doi: 10.1111/j.1476-5381.1993.tb13616.x

Oestradiol inhibits smooth muscle cell proliferation of pig coronary artery.

R Vargas 1, B Wroblewska 1, A Rego 1, J Hatch 1, P W Ramwell 1
PMCID: PMC2175627  PMID: 8358561

Abstract

1. The effect of oestradiol 17 beta 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 17 beta (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 significantly block oestradiol 17 beta-induced inhibition of thymidine uptake. 4. The LAD segments bound [3H]-oestradiol 17 beta in a time-dependent manner and about 20 to 30% was displaced by an excess of unlabelled oestradiol 17 beta. Autoradiography showed [3H]-oestradiol 17 beta was evenly distributed in the cytosol and nuclei of cells in the three layers of the vessel wall. 5. The data suggest that oestradiol 17 beta 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 17 beta in directly protecting coronary arteries against myointimal proliferation in premenopausal women.

Full text

PDF
614

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berthois Y., Katzenellenbogen J. A., Katzenellenbogen B. S. Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2496–2500. doi: 10.1073/pnas.83.8.2496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Breithardt G., Borggrefe M., Wichter T. Catheter ablation of idiopathic right ventricular tachycardia. Circulation. 1990 Dec;82(6):2273–2276. doi: 10.1161/01.cir.82.6.2273. [DOI] [PubMed] [Google Scholar]
  3. CONSTANTINIDES P., GUTMANN-AUERSPERGN, HOSPES D., WILLIAMS K. Estriol and prednisolone in rabbit atherosclerosis. Arch Pathol. 1962 Apr;73:277–280. [PubMed] [Google Scholar]
  4. Chang W. C., Nakao J., Orimo H., Murota S. Stimulation of prostacyclin biosynthetic activity by estradiol in rat aortic smooth muscle cells in culture. Biochim Biophys Acta. 1980 Jul 14;619(1):107–118. [PubMed] [Google Scholar]
  5. Cheng L. P., Kuwahara M., Jacobsson J., Foegh M. L. Inhibition of myointimal hyperplasia and macrophage infiltration by estradiol in aorta allografts. Transplantation. 1991 Dec;52(6):967–972. doi: 10.1097/00007890-199112000-00006. [DOI] [PubMed] [Google Scholar]
  6. Clarkson T. B., Adams M. R., Kaplan J. R., Koritnik D. R. Gonadal steroids in cardiac atherosclerosis in primates. Transplant Proc. 1987 Aug;19(4 Suppl 5):85–89. [PubMed] [Google Scholar]
  7. Clarkson T. B., Shively C. A., Morgan T. M., Koritnik D. R., Adams M. R., Kaplan J. R. Oral contraceptives and coronary artery atherosclerosis of cynomolgus monkeys. Obstet Gynecol. 1990 Feb;75(2):217–222. [PubMed] [Google Scholar]
  8. Clowes A. W., Reidy M. A., Clowes M. M. Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium. Lab Invest. 1983 Sep;49(3):327–333. [PubMed] [Google Scholar]
  9. Colburn P., Buonassisi V. Estrogen-binding sites in endothelial cell cultures. Science. 1978 Sep 1;201(4358):817–819. doi: 10.1126/science.684408. [DOI] [PubMed] [Google Scholar]
  10. Davidson N. E., Lippman M. E. The role of estrogens in growth regulation of breast cancer. Crit Rev Oncog. 1989;1(1):89–111. [PubMed] [Google Scholar]
  11. Diglio C. A., Grammas P., Giacomelli F., Wiener J. Rat heart-derived endothelial and smooth muscle cell cultures: isolation, cloning and characterization. Tissue Cell. 1988;20(4):477–492. doi: 10.1016/0040-8166(88)90051-1. [DOI] [PubMed] [Google Scholar]
  12. Fischer-Dzoga K., Wissler R. W., Vesselinovitch D. The effect of estradiol on the proliferation of rabbit aortic medial tissue culture cells induced by hyperlipemic serum. Exp Mol Pathol. 1983 Dec;39(3):355–363. doi: 10.1016/0014-4800(83)90064-3. [DOI] [PubMed] [Google Scholar]
  13. Fischer G. M., Swain M. L. Effects of estradiol and progesterone on the increased synthesis of collagen in atherosclerotic rabbit aortas. Atherosclerosis. 1985 Feb;54(2):177–185. doi: 10.1016/0021-9150(85)90177-7. [DOI] [PubMed] [Google Scholar]
  14. Foegh M. L., Khirabadi B. S., Nakanishi T., Vargas R., Ramwell P. W. Estradiol protects against experimental cardiac transplant atherosclerosis. Transplant Proc. 1987 Aug;19(4 Suppl 5):90–95. [PubMed] [Google Scholar]
  15. Friedman D. L. Role of cyclic nucleotides in cell growth and differentiation. Physiol Rev. 1976 Oct;56(4):652–708. doi: 10.1152/physrev.1976.56.4.652. [DOI] [PubMed] [Google Scholar]
  16. Garg U. C., Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989 May;83(5):1774–1777. doi: 10.1172/JCI114081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Haras D., Samperez S., Jouan P. Positive and negative effects of estradiol-17 beta in the rat uterus. J Steroid Biochem. 1989 Dec;33(6):1073–1080. doi: 10.1016/0022-4731(89)90411-1. [DOI] [PubMed] [Google Scholar]
  18. Harder D. R., Coulson P. B. Estrogen receptors and effects of estrogen on membrane electrical properties of coronary vascular smooth muscle. J Cell Physiol. 1979 Aug;100(2):375–382. doi: 10.1002/jcp.1041000218. [DOI] [PubMed] [Google Scholar]
  19. Jordan V. C. Biochemical pharmacology of antiestrogen action. Pharmacol Rev. 1984 Dec;36(4):245–276. [PubMed] [Google Scholar]
  20. Kempski O., Wroblewska B., Spatz M. Effects of forskolin on growth and morphology of cultured glial and cerebrovascular endothelial and smooth muscle cells. Int J Dev Neurosci. 1987;5(5-6):435–445. doi: 10.1016/0736-5748(87)90021-9. [DOI] [PubMed] [Google Scholar]
  21. Kocher O., Gabbiani G. Cytoskeletal features of normal and atheromatous human arterial smooth muscle cells. Hum Pathol. 1986 Sep;17(9):875–880. doi: 10.1016/s0046-8177(86)80637-2. [DOI] [PubMed] [Google Scholar]
  22. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  23. Lin A. L., Gonzalez R., Jr, Carey K. D., Shain S. A. Estradiol-17 beta affects estrogen receptor distribution and elevates progesterone receptor content in baboon aorta. Arteriosclerosis. 1986 Sep-Oct;6(5):495–504. doi: 10.1161/01.atv.6.5.495. [DOI] [PubMed] [Google Scholar]
  24. Lin A. L., McGill H. C., Jr, Shain S. A. Hormone receptors of the baboon cardiovascular system. Biochemical characterization of aortic and myocardial cytoplasmic progesterone receptors. Circ Res. 1982 May;50(5):610–616. doi: 10.1161/01.res.50.5.610. [DOI] [PubMed] [Google Scholar]
  25. Lin A. L., Shain S. A. Sexual dimorphism characterizes steroid hormone modulation of rat aortic steroid hormone receptors. Endocrinology. 1986 Jul;119(1):296–302. doi: 10.1210/endo-119-1-296. [DOI] [PubMed] [Google Scholar]
  26. MacIntyre D. E., Pearson J. D., Gordon J. L. Localisation and stimulation of prostacyclin production in vascular cells. Nature. 1978 Feb 9;271(5645):549–551. doi: 10.1038/271549a0. [DOI] [PubMed] [Google Scholar]
  27. Nakao J., Chang W. C., Murota S. I., Orimo H. Estradiol-binding sites in rat aortic smooth muscle cells in culture. Atherosclerosis. 1981 Jan-Feb;38(1-2):75–80. doi: 10.1016/0021-9150(81)90105-2. [DOI] [PubMed] [Google Scholar]
  28. Rhee C. Y., Spaet T. H., Stemerman M. B., Lajam F., Shiang H. H., Caruso E., Litwak R. S. Estrogen suppression of surgically induced vascular intimal hyperplasia in rabbits. J Lab Clin Med. 1977 Jul;90(1):77–84. [PubMed] [Google Scholar]
  29. Ross R., Glomset J. A. Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science. 1973 Jun 29;180(4093):1332–1339. doi: 10.1126/science.180.4093.1332. [DOI] [PubMed] [Google Scholar]
  30. Skalli O., Ropraz P., Trzeciak A., Benzonana G., Gillessen D., Gabbiani G. A monoclonal antibody against alpha-smooth muscle actin: a new probe for smooth muscle differentiation. J Cell Biol. 1986 Dec;103(6 Pt 2):2787–2796. doi: 10.1083/jcb.103.6.2787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Stumpf W. E., Sar M., Aumüller G. The heart: a target organ for estradiol. Science. 1977 Apr 15;196(4287):319–321. doi: 10.1126/science.847474. [DOI] [PubMed] [Google Scholar]
  32. Sutherland R. L., Reddel R. R., Green M. D. Effects of oestrogens on cell proliferation and cell cycle kinetics. A hypothesis on the cell cycle effects of antioestrogens. Eur J Cancer Clin Oncol. 1983 Mar;19(3):307–318. doi: 10.1016/0277-5379(83)90127-x. [DOI] [PubMed] [Google Scholar]
  33. Walker L. N., Bowen-Pope D. F., Ross R., Reidy M. A. Production of platelet-derived growth factor-like molecules by cultured arterial smooth muscle cells accompanies proliferation after arterial injury. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7311–7315. doi: 10.1073/pnas.83.19.7311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Welshons W. V., Wolf M. F., Murphy C. S., Jordan V. C. Estrogenic activity of phenol red. Mol Cell Endocrinol. 1988 Jun;57(3):169–178. doi: 10.1016/0303-7207(88)90072-x. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES