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. 1998 Jul 1;102(1):176–183. doi: 10.1172/JCI2034

Estrogen upregulates cyclooxygenase-1 gene expression in ovine fetal pulmonary artery endothelium.

S S Jun 1, Z Chen 1, M C Pace 1, P W Shaul 1
PMCID: PMC509079  PMID: 9649571

Abstract

Prostacyclin (PGI2) is a key mediator of pulmonary vasodilation in the perinatal period and its synthesis in the pulmonary vasculature increases markedly during late gestation due to enhanced expression of the rate-limiting enzyme cyclooxygenase-1 (COX-1). The hormone estrogen may play a role in COX-1 upregulation since fetal estrogen levels rise dramatically during late gestation and estrogen enhances PGI2 synthesis in nonpulmonary vascular cells. We therefore studied the direct effects of estrogen on COX-1 expression in ovine fetal pulmonary artery endothelial cells (PAEC). Exposure to estradiol-17beta (E2beta, 10(-)10 to 10(-)6 M) caused a dose-related increase in COX-1 mRNA expression that was evident after 48 h and maximal at 10(-)8 M (fourfold increase). COX-1 mRNA stability was unchanged, suggesting that the upregulation is mediated at the level of transcription. E2beta treatment (10(-)8 M for 48 h) also caused a threefold increase in COX-1 protein expression and a threefold increase in PGI2 synthesis stimulated by bradykinin, the calcium ionophore A23187, or arachidonic acid. The estrogen receptor (ER) antagonist ICI 182,780 fully reversed the effects of the hormone on COX-1 protein expression and on arachidonic acid-stimulated PGI2 synthesis, and ER expression was evident in the PAEC by immunoblot analysis. These findings indicate that physiologic levels of estrogen cause upregulation of COX-1 expression and PGI2 synthesis in fetal PAEC via activation of PAEC ER. This process may play a critical role in optimizing the capacity for PGI2-mediated pulmonary vasodilation at birth, and it may also be involved in estrogen responsiveness in other vascular beds.

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Selected References

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  1. Acarregui M. J., Snyder J. M., Mitchell M. D., Mendelson C. R. Prostaglandins regulate surfactant protein A (SP-A) gene expression in human fetal lung in vitro. Endocrinology. 1990 Sep;127(3):1105–1113. doi: 10.1210/endo-127-3-1105. [DOI] [PubMed] [Google Scholar]
  2. Barnhart B. J., Carlson C. V., Reynolds J. W. Adrenal cortical function in the postmature fetus and newborn infant. Pediatr Res. 1980 Dec;14(12):1367–1369. doi: 10.1203/00006450-198012000-00021. [DOI] [PubMed] [Google Scholar]
  3. Barrett-Connor E., Bush T. L. Estrogen and coronary heart disease in women. JAMA. 1991 Apr 10;265(14):1861–1867. [PubMed] [Google Scholar]
  4. Brannon T. S., North A. J., Wells L. B., Shaul P. W. Prostacyclin synthesis in ovine pulmonary artery is developmentally regulated by changes in cyclooxygenase-1 gene expression. J Clin Invest. 1994 May;93(5):2230–2235. doi: 10.1172/JCI117220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bush T. L., Barrett-Connor E., Cowan L. D., Criqui M. H., Wallace R. B., Suchindran C. M., Tyroler H. A., Rifkind B. M. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation. 1987 Jun;75(6):1102–1109. doi: 10.1161/01.cir.75.6.1102. [DOI] [PubMed] [Google Scholar]
  6. Carnegie J. A., Robertson H. A. Conjugated and unconjugated estrogens in fetal and maternal fluids of the pregnant ewe: a possible role for estrone sulfate during early pregnancy. Biol Reprod. 1978 Aug;19(1):202–211. doi: 10.1095/biolreprod19.1.202. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Darbre P., Yates J., Curtis S., King R. J. Effect of estradiol on human breast cancer cells in culture. Cancer Res. 1983 Jan;43(1):349–354. [PubMed] [Google Scholar]
  9. Frangos J. A., Eskin S. G., McIntire L. V., Ives C. L. Flow effects on prostacyclin production by cultured human endothelial cells. Science. 1985 Mar 22;227(4693):1477–1479. doi: 10.1126/science.3883488. [DOI] [PubMed] [Google Scholar]
  10. Fujimoto J., Ichigo S., Hori M., Morishita S., Tamaya T. Estrogen induces c-Ha-ras expression via activation of tyrosine kinase in uterine endometrial fibroblasts and cancer cells. J Steroid Biochem Mol Biol. 1995 Oct;55(1):25–33. doi: 10.1016/0960-0760(95)00145-p. [DOI] [PubMed] [Google Scholar]
  11. Gelly C., Sumida C., Gulino A., Pasqualini J. R. Concentrations of oestradiol and oestrone in plasma, uterus and other tissues of fetal guinea-pigs: their relationship to uptake and specific binding of [3H]oestradiol. J Endocrinol. 1981 Apr;89(1):71–77. doi: 10.1677/joe.0.0890071. [DOI] [PubMed] [Google Scholar]
  12. Gravett M. G., Haluska G. J., Cook M. J., Novy M. J. Fetal and maternal endocrine responses to experimental intrauterine infection in rhesus monkeys. Am J Obstet Gynecol. 1996 Jun;174(6):1725–1733. doi: 10.1016/s0002-9378(96)70203-x. [DOI] [PubMed] [Google Scholar]
  13. Kato S., Tora L., Yamauchi J., Masushige S., Bellard M., Chambon P. A far upstream estrogen response element of the ovalbumin gene contains several half-palindromic 5'-TGACC-3' motifs acting synergistically. Cell. 1992 Feb 21;68(4):731–742. doi: 10.1016/0092-8674(92)90148-6. [DOI] [PubMed] [Google Scholar]
  14. Kuiper G. G., Carlsson B., Grandien K., Enmark E., Häggblad J., Nilsson S., Gustafsson J. A. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology. 1997 Mar;138(3):863–870. doi: 10.1210/endo.138.3.4979. [DOI] [PubMed] [Google Scholar]
  15. Kuiper G. G., Enmark E., Pelto-Huikko M., Nilsson S., Gustafsson J. A. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5925–5930. doi: 10.1073/pnas.93.12.5925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. L'Horset F., Blin C., Colnot S., Lambert M., Thomasset M., Perret C. Calbindin-D9k gene expression in the uterus: study of the two messenger ribonucleic acid species and analysis of an imperfect estrogen-responsive element. Endocrinology. 1994 Jan;134(1):11–18. doi: 10.1210/endo.134.1.7506202. [DOI] [PubMed] [Google Scholar]
  17. Leffler C. W., Hessler J. R. Pulmonary and systemic vascular effects of exogenous prostaglandin I2 in fetal lambs. Eur J Pharmacol. 1979 Feb 15;54(1-2):37–42. doi: 10.1016/0014-2999(79)90405-9. [DOI] [PubMed] [Google Scholar]
  18. Lock J. E., Olley P. M., Soldin S., Coceani F. Indomethacin-induced pulmonary vasoconstriction in the conscious newborn lamb. Am J Physiol. 1980 May;238(5):H639–H651. doi: 10.1152/ajpheart.1980.238.5.H639. [DOI] [PubMed] [Google Scholar]
  19. Magness R. R., Mitchell M. D., Rosenfeld C. R. Uteroplacental production of eicosanoids in ovine pregnancy. Prostaglandins. 1990 Jan;39(1):75–88. doi: 10.1016/0090-6980(90)90096-e. [DOI] [PubMed] [Google Scholar]
  20. Magness R. R., Rosenfeld C. R., Hassan A., Shaul P. W. Endothelial vasodilator production by uterine and systemic arteries. I. Effects of ANG II on PGI2 and NO in pregnancy. Am J Physiol. 1996 Jun;270(6 Pt 2):H1914–H1923. doi: 10.1152/ajpheart.1996.270.6.H1914. [DOI] [PubMed] [Google Scholar]
  21. Mendelsohn M. E., Karas R. H. Estrogen and the blood vessel wall. Curr Opin Cardiol. 1994 Sep;9(5):619–626. doi: 10.1097/00001573-199409000-00018. [DOI] [PubMed] [Google Scholar]
  22. Merlie J. P., Fagan D., Mudd J., Needleman P. Isolation and characterization of the complementary DNA for sheep seminal vesicle prostaglandin endoperoxide synthase (cyclooxygenase). J Biol Chem. 1988 Mar 15;263(8):3550–3553. [PubMed] [Google Scholar]
  23. Meyrick B., Niedermeyer M. E., Ogletree M. L., Brigham K. L. Pulmonary hypertension and increased vasoreactivity caused by repeated indomethacin in sheep. J Appl Physiol (1985) 1985 Aug;59(2):443–452. doi: 10.1152/jappl.1985.59.2.443. [DOI] [PubMed] [Google Scholar]
  24. Migliaccio A., Di Domenico M., Castoria G., de Falco A., Bontempo P., Nola E., Auricchio F. Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. EMBO J. 1996 Mar 15;15(6):1292–1300. [PMC free article] [PubMed] [Google Scholar]
  25. Moonen P., Klok G., Keirse M. J. Increase in concentrations of prostaglandin endoperoxide synthase and prostacyclin synthase in human myometrium in late pregnancy. Prostaglandins. 1984 Sep;28(3):309–321. doi: 10.1016/0090-6980(84)90019-4. [DOI] [PubMed] [Google Scholar]
  26. Mosselman S., Polman J., Dijkema R. ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett. 1996 Aug 19;392(1):49–53. doi: 10.1016/0014-5793(96)00782-x. [DOI] [PubMed] [Google Scholar]
  27. Murdoch F. E., Byrne L. M., Ariazi E. A., Furlow J. D., Meier D. A., Gorski J. Estrogen receptor binding to DNA: affinity for nonpalindromic elements from the rat prolactin gene. Biochemistry. 1995 Jul 18;34(28):9144–9150. doi: 10.1021/bi00028a025. [DOI] [PubMed] [Google Scholar]
  28. Myers S. I., Turnage R. H., Bartula L., Kalley B., Meng Y. Estrogen increases male rat aortic endothelial cell (RAEC) PGI2 release. Prostaglandins Leukot Essent Fatty Acids. 1996 Jun;54(6):403–409. doi: 10.1016/s0952-3278(96)90023-x. [DOI] [PubMed] [Google Scholar]
  29. North A. J., Brannon T. S., Wells L. B., Campbell W. B., Shaul P. W. Hypoxia stimulates prostacyclin synthesis in newborn pulmonary artery endothelium by increasing cyclooxygenase-1 protein. Circ Res. 1994 Jul;75(1):33–40. doi: 10.1161/01.res.75.1.33. [DOI] [PubMed] [Google Scholar]
  30. North A. J., Star R. A., Brannon T. S., Ujiie K., Wells L. B., Lowenstein C. J., Snyder S. H., Shaul P. W. Nitric oxide synthase type I and type III gene expression are developmentally regulated in rat lung. Am J Physiol. 1994 Jun;266(6 Pt 1):L635–L641. doi: 10.1152/ajplung.1994.266.6.L635. [DOI] [PubMed] [Google Scholar]
  31. O'Hagan R. C., Tozer R. G., Symons M., McCormick F., Hassell J. A. The activity of the Ets transcription factor PEA3 is regulated by two distinct MAPK cascades. Oncogene. 1996 Sep 19;13(6):1323–1333. [PubMed] [Google Scholar]
  32. Pace-Asciak C. R. Prostaglandin biosynthesis and catabolism in the developing fetal sheep lung. Prostaglandins. 1977 Apr;13(4):649–660. doi: 10.1016/0090-6980(77)90235-0. [DOI] [PubMed] [Google Scholar]
  33. Powell W. S., Solomon S. Biosynthesis of prostaglandins and thromboxane B2 by fetal lung homogenates. Prostaglandins. 1978 Feb;15(2):351–364. doi: 10.1016/0090-6980(78)90175-2. [DOI] [PubMed] [Google Scholar]
  34. Printz M. P., Skidgel R. A., Friedman W. F. Studies of pulmonary prostaglandin biosynthetic and catabolic enzymes as factors in ductus arteriosus patency and closure. Evidence for a shift in products with gestational age. Pediatr Res. 1984 Jan;18(1):19–24. [PubMed] [Google Scholar]
  35. Rabinovitch M., Gamble W. J., Miettinen O. S., Reid L. Age and sex influence on pulmonary hypertension of chronic hypoxia and on recovery. Am J Physiol. 1981 Jan;240(1):H62–H72. doi: 10.1152/ajpheart.1981.240.1.H62. [DOI] [PubMed] [Google Scholar]
  36. Robertson H. A., Dwyer R. J., King G. J. Oestrogens in fetal and maternal fluids throughout pregnancy in the pig and comparisons with the ewe and cow. J Endocrinol. 1985 Sep;106(3):355–360. doi: 10.1677/joe.0.1060355. [DOI] [PubMed] [Google Scholar]
  37. Schwartz G. J., Zavilowitz B. J., Radice A. D., Garcia-Perez A., Sands J. M. Maturation of aldose reductase expression in the neonatal rat inner medulla. J Clin Invest. 1992 Oct;90(4):1275–1283. doi: 10.1172/JCI115991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Seillan C., Ody C., Russo-Marie F., Duval D. Differential effects of sex steroids on prostaglandin secretion by male and female cultured piglet endothelial cells. Prostaglandins. 1983 Jul;26(1):3–12. doi: 10.1016/0090-6980(83)90069-2. [DOI] [PubMed] [Google Scholar]
  39. Shaul P. W., North A. J., Brannon T. S., Ujiie K., Wells L. B., Nisen P. A., Lowenstein C. J., Snyder S. H., Star R. A. Prolonged in vivo hypoxia enhances nitric oxide synthase type I and type III gene expression in adult rat lung. Am J Respir Cell Mol Biol. 1995 Aug;13(2):167–174. doi: 10.1165/ajrcmb.13.2.7542896. [DOI] [PubMed] [Google Scholar]
  40. Smith W. L. Prostaglandin biosynthesis and its compartmentation in vascular smooth muscle and endothelial cells. Annu Rev Physiol. 1986;48:251–262. doi: 10.1146/annurev.ph.48.030186.001343. [DOI] [PubMed] [Google Scholar]
  41. Steinleitner A., Stanczyk F. Z., Levin J. H., d'Ablaing G., 3rd, Vijod M. A., Shahbazian V. L., Lobo R. A. Decreased in vitro production of 6-keto-prostaglandin F1 alpha by uterine arteries from postmenopausal women. Am J Obstet Gynecol. 1989 Dec;161(6 Pt 1):1677–1681. doi: 10.1016/0002-9378(89)90949-6. [DOI] [PubMed] [Google Scholar]
  42. Wang L. H., Hajibeigi A., Xu X. M., Loose-Mitchell D., Wu K. K. Characterization of the promoter of human prostaglandin H synthase-1 gene. Biochem Biophys Res Commun. 1993 Jan 29;190(2):406–411. doi: 10.1006/bbrc.1993.1062. [DOI] [PubMed] [Google Scholar]
  43. Weiss H. J., Turitto V. T. Prostacyclin (prostaglandin I2, PGI2) inhibits platelet adhesion and thrombus formation on subendothelium. Blood. 1979 Feb;53(2):244–250. [PubMed] [Google Scholar]
  44. Xu X. M., Tang J. L., Chen X., Wang L. H., Wu K. K. Involvement of two Sp1 elements in basal endothelial prostaglandin H synthase-1 promoter activity. J Biol Chem. 1997 Mar 14;272(11):6943–6950. doi: 10.1074/jbc.272.11.6943. [DOI] [PubMed] [Google Scholar]

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