Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Sep 15;100(6):1406–1415. doi: 10.1172/JCI119661

Angiotensinogen T235 expression is elevated in decidual spiral arteries.

T Morgan 1, C Craven 1, L Nelson 1, J M Lalouel 1, K Ward 1
PMCID: PMC508319  PMID: 9294106

Abstract

Preeclampsia is associated with a common molecular variant of angiotensinogen (Met235Thr). This variant is in tight linkage disequilibrium with a mutation in the angiotensinogen promoter, G(-6)A, which leads to elevated expression in vitro. Since angiotensin II levels could play a role in atherotic changes of the uterine spiral arteries associated with preeclampsia, we investigated angiotensinogen expression in the first trimester uterus. We localized angiotensinogen transcription in uterine decidua using in situ reverse transcription PCR. We then compared decidual T235 expression levels to M235 levels in heterozygous women using an allele-specific ligation assay and a single nucleotide primer extension assay. In human decidua, angiotensinogen is expressed only in spiral artery smooth muscle cells. Heterozygous women have significantly elevated expression of the T235 allele compared to the M235 allele (P < 0.0001). These observations suggest that elevated expression of the T235 allele in decidual spiral arteries may cause first trimester atherotic changes leading to preeclampsia.

Full Text

The Full Text of this article is available as a PDF (420.9 KB).

Selected References

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

  1. Alhenc-Gelas F., Richard J., Courbon D., Warnet J. M., Corvol P. Distribution of plasma angiotensin I-converting enzyme levels in healthy men: relationship to environmental and hormonal parameters. J Lab Clin Med. 1991 Jan;117(1):33–39. [PubMed] [Google Scholar]
  2. Arngrímsson R., Purandare S., Connor M., Walker J. J., Björnsson S., Soubrier F., Kotelevtsev Y. V., Geirsson R. T., Björnsson H. Angiotensinogen: a candidate gene involved in preeclampsia? Nat Genet. 1993 Jun;4(2):114–115. doi: 10.1038/ng0693-114. [DOI] [PubMed] [Google Scholar]
  3. BULFIN M. J., LAWLER P. E. Problems associated with toxemia in twin pregnancies. Am J Obstet Gynecol. 1957 Jan;73(1):37–42. doi: 10.1016/s0002-9378(16)37264-7. [DOI] [PubMed] [Google Scholar]
  4. Berk B. C., Vekshtein V., Gordon H. M., Tsuda T. Angiotensin II-stimulated protein synthesis in cultured vascular smooth muscle cells. Hypertension. 1989 Apr;13(4):305–314. doi: 10.1161/01.hyp.13.4.305. [DOI] [PubMed] [Google Scholar]
  5. Brosens I. A., Robertson W. B., Dixon H. G. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu. 1972;1:177–191. [PubMed] [Google Scholar]
  6. Brosens I., Robertson W. B., Dixon H. G. The physiological response of the vessels of the placental bed to normal pregnancy. J Pathol Bacteriol. 1967 Apr;93(2):569–579. doi: 10.1002/path.1700930218. [DOI] [PubMed] [Google Scholar]
  7. CHESLEY L. C., COSGROVE R. A., ANNITTO J. E. Pregnancy in the sisters and daughters of eclamptic women. Pathol Microbiol (Basel) 1961;24:662–666. doi: 10.1159/000161178. [DOI] [PubMed] [Google Scholar]
  8. Campbell D. J. Circulating and tissue angiotensin systems. J Clin Invest. 1987 Jan;79(1):1–6. doi: 10.1172/JCI112768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chomczynski P. A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. Biotechniques. 1993 Sep;15(3):532-4, 536-7. [PubMed] [Google Scholar]
  10. Dzau V. J., Gibbons G. H., Pratt R. E. Molecular mechanisms of vascular renin-angiotensin system in myointimal hyperplasia. Hypertension. 1991 Oct;18(4 Suppl):II100–II105. doi: 10.1161/01.hyp.18.4_suppl.ii100. [DOI] [PubMed] [Google Scholar]
  11. Fukamizu A., Takahashi S., Seo M. S., Tada M., Tanimoto K., Uehara S., Murakami K. Structure and expression of the human angiotensinogen gene. Identification of a unique and highly active promoter. J Biol Chem. 1990 May 5;265(13):7576–7582. [PubMed] [Google Scholar]
  12. Gaillard I., Clauser E., Corvol P. Structure of human angiotensinogen gene. DNA. 1989 Mar;8(2):87–99. doi: 10.1089/dna.1.1989.8.87. [DOI] [PubMed] [Google Scholar]
  13. Gant N. F., Madden J. D., Chand S., Worley R. J., Siiteri P. K., MacDonald P. C. Metabolic clearance rate of dehydroisoandrosterone sulfate. VI. Studies of eclampsia. Obstet Gynecol. 1976 Mar;47(3):327–330. [PubMed] [Google Scholar]
  14. Inoue I., Nakajima T., Williams C. S., Quackenbush J., Puryear R., Powers M., Cheng T., Ludwig E. H., Sharma A. M., Hata A. A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J Clin Invest. 1997 Apr 1;99(7):1786–1797. doi: 10.1172/JCI119343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ishigami T., Umemura S., Iwamoto T., Tamura K., Hibi K., Yamaguchi S., Nyuui N., Kimura K., Miyazaki N., Ishii M. Molecular variant of angiotensinogen gene is associated with coronary atherosclerosis. Circulation. 1995 Feb 15;91(4):951–954. doi: 10.1161/01.cir.91.4.951. [DOI] [PubMed] [Google Scholar]
  16. Jeunemaitre X., Soubrier F., Kotelevtsev Y. V., Lifton R. P., Williams C. S., Charru A., Hunt S. C., Hopkins P. N., Williams R. R., Lalouel J. M. Molecular basis of human hypertension: role of angiotensinogen. Cell. 1992 Oct 2;71(1):169–180. doi: 10.1016/0092-8674(92)90275-h. [DOI] [PubMed] [Google Scholar]
  17. Kobashi G. [A case-control study of pregnancy-induced hypertension with a genetic predisposition: association of a molecular variant of angiotensinogen in the Japanese women]. Hokkaido Igaku Zasshi. 1995 Jul;70(4):649–657. [PubMed] [Google Scholar]
  18. Labarrere C. A., Faulk W. P. Antigenic identification of cells in spiral artery trophoblastic invasion: validation of histologic studies by triple-antibody immunocytochemistry. Am J Obstet Gynecol. 1994 Jul;171(1):165–171. doi: 10.1016/0002-9378(94)90464-2. [DOI] [PubMed] [Google Scholar]
  19. Lichtig C., Deutch M., Brandes J. Vascular changes of endometrium in early pregnancy. Am J Clin Pathol. 1984 Jun;81(6):702–707. doi: 10.1093/ajcp/81.6.702. [DOI] [PubMed] [Google Scholar]
  20. Morgan L., Baker P., Broughton Pipkin F., Kalsheker N. Pre-eclampsia and the angiotensinogen gene. Br J Obstet Gynaecol. 1995 Jun;102(6):489–490. doi: 10.1111/j.1471-0528.1995.tb11324.x. [DOI] [PubMed] [Google Scholar]
  21. Ménard J., Bouhnik J., Clauser E., Richoux J. P., Corvol P. Biochemistry and regulation of angiotensinogen. Clin Exp Hypertens A. 1983;5(7-8):1005–1019. doi: 10.3109/10641968309048838. [DOI] [PubMed] [Google Scholar]
  22. Nadji P., Sommers S. C. Lesions of toxemia in first trimester pregnancies. Am J Clin Pathol. 1973 Mar;59(3):344–349. doi: 10.1093/ajcp/59.3.344. [DOI] [PubMed] [Google Scholar]
  23. Naftilan A. J., Pratt R. E., Dzau V. J. Induction of platelet-derived growth factor A-chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth muscle cells. J Clin Invest. 1989 Apr;83(4):1419–1424. doi: 10.1172/JCI114032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Naftilan A. J., Zuo W. M., Inglefinger J., Ryan T. J., Jr, Pratt R. E., Dzau V. J. Localization and differential regulation of angiotensinogen mRNA expression in the vessel wall. J Clin Invest. 1991 Apr;87(4):1300–1311. doi: 10.1172/JCI115133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. North R. A., Ferrier C., Long D., Townend K., Kincaid-Smith P. Uterine artery Doppler flow velocity waveforms in the second trimester for the prediction of preeclampsia and fetal growth retardation. Obstet Gynecol. 1994 Mar;83(3):378–386. [PubMed] [Google Scholar]
  26. Paul M., Wagner J., Dzau V. J. Gene expression of the renin-angiotensin system in human tissues. Quantitative analysis by the polymerase chain reaction. J Clin Invest. 1993 May;91(5):2058–2064. doi: 10.1172/JCI116428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Perrot-Applanat M., Deng M., Fernandez H., Lelaidier C., Meduri G., Bouchard P. Immunohistochemical localization of estradiol and progesterone receptors in human uterus throughout pregnancy: expression in endometrial blood vessels. J Clin Endocrinol Metab. 1994 Jan;78(1):216–224. doi: 10.1210/jcem.78.1.8288707. [DOI] [PubMed] [Google Scholar]
  28. Pijnenborg R., Anthony J., Davey D. A., Rees A., Tiltman A., Vercruysse L., van Assche A. Placental bed spiral arteries in the hypertensive disorders of pregnancy. Br J Obstet Gynaecol. 1991 Jul;98(7):648–655. doi: 10.1111/j.1471-0528.1991.tb13450.x. [DOI] [PubMed] [Google Scholar]
  29. Pijnenborg R., Bland J. M., Robertson W. B., Brosens I. Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta. 1983 Oct-Dec;4(4):397–413. doi: 10.1016/s0143-4004(83)80043-5. [DOI] [PubMed] [Google Scholar]
  30. Pijnenborg R., Dixon G., Robertson W. B., Brosens I. Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy. Placenta. 1980 Jan-Mar;1(1):3–19. doi: 10.1016/s0143-4004(80)80012-9. [DOI] [PubMed] [Google Scholar]
  31. Poulsen K. Kinetics of the renin system. The basis for determination of the different components of the system. Scand J Clin Lab Invest Suppl. 1973;132:3–86. [PubMed] [Google Scholar]
  32. Powell J. S., Clozel J. P., Müller R. K., Kuhn H., Hefti F., Hosang M., Baumgartner H. R. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science. 1989 Jul 14;245(4914):186–188. doi: 10.1126/science.2526370. [DOI] [PubMed] [Google Scholar]
  33. Powell S. M., Petersen G. M., Krush A. J., Booker S., Jen J., Giardiello F. M., Hamilton S. R., Vogelstein B., Kinzler K. W. Molecular diagnosis of familial adenomatous polyposis. N Engl J Med. 1993 Dec 30;329(27):1982–1987. doi: 10.1056/NEJM199312303292702. [DOI] [PubMed] [Google Scholar]
  34. Redman C. W. Current topic: pre-eclampsia and the placenta. Placenta. 1991 Jul-Aug;12(4):301–308. doi: 10.1016/0143-4004(91)90339-h. [DOI] [PubMed] [Google Scholar]
  35. Roberts J. M., Taylor R. N., Musci T. J., Rodgers G. M., Hubel C. A., McLaughlin M. K. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989 Nov;161(5):1200–1204. doi: 10.1016/0002-9378(89)90665-0. [DOI] [PubMed] [Google Scholar]
  36. Rust S., Funke H., Assmann G. Mutagenically separated PCR (MS-PCR): a highly specific one step procedure for easy mutation detection. Nucleic Acids Res. 1993 Aug 11;21(16):3623–3629. doi: 10.1093/nar/21.16.3623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schweikhart G., Kaufmann P., Beck T. Morphology of placental villi after premature delivery and its clinical relevance. Arch Gynecol. 1986;239(2):101–114. doi: 10.1007/BF02133969. [DOI] [PubMed] [Google Scholar]
  38. Singer-Sam J., Riggs A. D. Quantitative analysis of messenger RNA levels: reverse transcription-polymerase chain reaction single nucleotide primer extension assay. Methods Enzymol. 1993;225:344–351. doi: 10.1016/0076-6879(93)25023-u. [DOI] [PubMed] [Google Scholar]
  39. Takimoto E., Ishida J., Sugiyama F., Horiguchi H., Murakami K., Fukamizu A. Hypertension induced in pregnant mice by placental renin and maternal angiotensinogen. Science. 1996 Nov 8;274(5289):995–998. doi: 10.1126/science.274.5289.995. [DOI] [PubMed] [Google Scholar]
  40. Tarnow L., Cambien F., Rossing P., Nielsen F. S., Hansen B. V., Ricard S., Poirier O., Parving H. H. Angiotensinogen gene polymorphisms in IDDM patients with diabetic nephropathy. Diabetes. 1996 Mar;45(3):367–369. doi: 10.2337/diab.45.3.367. [DOI] [PubMed] [Google Scholar]
  41. Tewksbury D. A. Angiotensinogen. Fed Proc. 1983 Jul;42(10):2724–2728. [PubMed] [Google Scholar]
  42. Ward K., Hata A., Jeunemaitre X., Helin C., Nelson L., Namikawa C., Farrington P. F., Ogasawara M., Suzumori K., Tomoda S. A molecular variant of angiotensinogen associated with preeclampsia. Nat Genet. 1993 May;4(1):59–61. doi: 10.1038/ng0593-59. [DOI] [PubMed] [Google Scholar]
  43. Wilcox J. N. Fundamental principles of in situ hybridization. J Histochem Cytochem. 1993 Dec;41(12):1725–1733. doi: 10.1177/41.12.8245419. [DOI] [PubMed] [Google Scholar]
  44. Yanai K., Nibu Y., Murakami K., Fukamizu A. A cis-acting DNA element located between TATA box and transcription initiation site is critical in response to regulatory sequences in human angiotensinogen gene. J Biol Chem. 1996 Jul 5;271(27):15981–15986. doi: 10.1074/jbc.271.27.15981. [DOI] [PubMed] [Google Scholar]
  45. ZEEK P. M., ASSALI N. S. Vascular changes in the decidua associated with eclamptogenic toxemia of pregnancy. Am J Clin Pathol. 1950 Dec;20(12):1099–1109. doi: 10.1093/ajcp/20.12.1099. [DOI] [PubMed] [Google Scholar]
  46. Zamudio S., Palmer S. K., Dahms T. E., Berman J. C., Young D. A., Moore L. G. Alterations in uteroplacental blood flow precede hypertension in preeclampsia at high altitude. J Appl Physiol (1985) 1995 Jul;79(1):15–22. doi: 10.1152/jappl.1995.79.1.15. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES