Estrogen Decreases Prostaglandin H Synthase Products From Endothelial Cells

Abstract

Objective: Because we showed recently that estrogen replacement prevents prostaglandin H synthase (PGHS)—dependent vasoconstriction in rats, the aim of this study was to determine how estradiol affects production of PGHS-dependent eicosanoids.

Methods: Cultured bovine coronary microvascular endothelial cells were exposed to physiologic levels of 17β-estradiol (0.01nM [about 2.7 pg/mL], 0.1 nM [about 27 pg/mL], or 1.0 nM [about 270 pg/mL]) for 4, 8, or 24 hours. Thromboxane (TXA₂), prostacyclin (PGI₂), and nitric oxide (NO) were measured as their stable metabolites, thromboxane B₂ (TXB₂), 6-keto prostaglandin F_1α (6-keto PGF_1α), and nitrite (NO₂), respectively.

Results: Estradiol had no effect on nitrite production. However, exposure to 0.1 nM and 1.0 nM estradiol for 24 hours reduced TXB₂ production to 67 ± 16% and 69 ± 12% of control, respectively. Furthermore, 0.1 nM and 1.0 nM estradiol also reduced production of 6-keto PGF_1α to 35 ± 19% and 17 ± 11% of control, respectively. Prostaglandin H synthase expression was not altered by estradiol. However, the estrogen receptor inhibitor, tamoxifen, reversed the inhibitory effect of estradiol.

Conclusion: Estradiol acts through a receptor-dependent process to decrease PGHS-dependent products, thus further elucidating this novel effect of estradiol on the vascular system.

Keywords

Estrogen eicosanoids vasoconstrictor endothelium vascular prostaglandin H synthase

Get full access to this article

View all access options for this article.

References

1. Wenger NK . Cardiovascular disease in the elderly. Curr Probl Cardiol 1992;17:609-690.

2. Caulin-Glaser T , Garcia-Cardena G , Sarrel P , Sessa WC , Bender JR . 17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization. Circ Res 1997;81:885-892.

3. Weiner CP , Lizasoain I , Baylis SA , Knowles RG , Charles IG , Moncada S . Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci U S A 1994;91:5212-5216.

4. Kauser K , Rubanyi GM . Gender difference in endothelial dysfunction in the aorta of spontaneously hypertensive rats. Hypertension 1995;25:517-523.

5. Kato T , Iwama Y , Okumura K , Hashimoto H , Ito T , Satake T . Prostaglandin H2 may be the endothelium-derived contracting factor released by acetylcholine in the aorta of the rat. Hypertension 1990;15:475-481.

6. Davidge ST , Hubel CA , McLaughlin MK . Impairment of vascular function is associated with an age-related increase of lipid peroxidation in rats. Am J Physiol 1996;271:R1625-R1631.

7. Davidge S , Zhang Y . Estrogen replacement suppresses a prostaglandin H synthase-dependent vasoconstrictor in rat mesenteric arteries. Circ Res 1998;83:388-395.

8. Bradford MM . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248-254.

9. Green LC , Wagner DA , Glogowski J , Skipper PL , Wishnok JS , Tannenbaum SR . Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 1982;126:131-138.

10.

10. Laemmli UK . Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970;227:680-685.

11.

11. Rodriguez-Martinez MA , Garcia-Cohen EC , Baena AB , Gonzalez R , Salaices M , Marin J . Contractile responses elicited by hydrogen peroxide in aorta from normotensive and hypertensive rats. Endothelial modulation and mechanism involved. Br J Pharmacol 1998;125:1329-1335.

12.

12. Koga T , Takata Y , Kobayashi K , Takishita S , Yamashita Y , Fujishima M . Age and hypertension promote endothelium-dependent contractions to acetylcholine in the aorta of the rat. Hypertension 1989;14:542-548.

13.

13. Zerrouk A , Auguet M , Chabrier PE . Augmented endothelium-dependent contraction to angioensin II in the SHR aorta: Role of an inducible cyclooxygenase metabolite. J Cardiovasc Pharmacol 1998;31:525-533.

14.

14. Ermert L , Ermert M , Althoff A , Merkle M , Grimminger F , Seeger W . Vasoregulatory prostanoid generation proceeds via cyclooxygenase-2 in noninflamed rat lungs. J Pharmacol Exp Ther 1998;286:1309-1314.

15.

15. Ge T , Hughes H , Junquero DC , Wu KK , Vanhoutte PM , Boulanger CM . Endothelium-dependent contractions are associated with both augmented expression of prostaglandin H synthase-1 and hypersensitivity to prostaglandin H2 in the SHR aorta. Circ Res 1995:76:1003-1010.

16.

16. Davidge ST , Hubel CA , McLaughlin MK . Cyclooxygenase-dependent vasoconstrictor alters vascular function in the vitamin E-deprived rat. Circ Res 1993;73:79-88.

17.

17. Luscher TF , Vanhoutte PM . Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension 1986;8:344-348.

18.

18. Jordan VC . Biochemical pharmacology of antiestrogen action. Pharmacol Rev 1984;36:245-276.

19.

19. Ghanam K , Javellaud J , Ea-Kim L , Oudart N . The protective effect of 17 beta-estradiol on vasomotor responses of aorta from cholesterol-fed rabbit is reduced by inhibitors of superoxide dismutase and catalase. Biochem Biophys Res Commun 1998;249:858-864.

20.

20. Kim YD , Farhat MY , Myers AK , et al. 17-Beta estradiol regulation of myocardial glutathione and its role in protection against myocardial stunning in dogs. J Cardiovasc Pharmacol 1998;32:457-465.

21.

21. Massafra C , De Felice C , Gioia D , Buonocore G . Variations in erythrocyte antioxidant glutathione peroxidase activity during the menstrual cycle. Clin Endocrinol (Oxf) 1998;49:63-67.

22.

22. Davidge ST , Baker PN , Laughlin MK , Roberts JM . Nitric oxide produced by endothelial cells increases production of eicosanoids through activation of prostaglandin H synthase. Circ Res 1995;77:274-283.

23.

23. Tetsuka T , Daphna-Iken D , Miller BW , Guan Z , Baier LD , Morrison AR . Nitric oxide amplifies interleukin 1-induced cyclooxygenase-2 expression in rat mesangial cells. J Clin Invest 1996;97:2051-2056.

24.

24. Hayashi T , Fukuto JM , Ignarro LJ , Chaudhuri G . Basal release of nitric oxide from aortic rings is greater in female rabbits than in male rabbits: Implications for atherosclerosis. Proc Natl Acad Sci U S A 1992;89:11259-11263.

25.

25. Cicinelli E , Ignarro LJ , Lograno M , Galantino P , Balzano G , Schonauer LM . Circulating levels of nitric oxide in fertile women in relation to the menstrual cycle. Fertil Steril 1996;66:1036-1038.

26.

26. Myers SI , Turnage RH , Bartula L , Kalley B , Meng Y . Estrogen increases male rat aortic endothelial cell (RAEC) PGI2 release. Prostaglandins Leukot Essent Fatty Acids 1996;54:403-409.

27.

27. Thorin E , Shatos MA , Shreeve SM , Walters CL , Bevan JA . Human vascular endothelium heterogeneity. A comparative study of cerebral and peripheral cultured vascular endothelial cells. Storke 1997;28:375-381.

28.

28. Chen L , McNeill JR , Wilson TW , Gopalakrishnan V . Heterogeneity in vascular smooth muscle responsiveness to angiotensin II. Role of endothelin. Hypertension 1995;26:83-88.

29.

29. Salvemini D , Seibert K , Masferrer JL , Misko TP , Currie MG , Needleman P . Endogenous nitric oxide enhances prostaglandin production in a model of renal inflammation. J Clin Invest 1994;93:1940-1947.