Skip to main content

Advertisement

SpringerLink
Log in

Hypertension in an Animal Model of HELLP Syndrome is Associated With Activation of Endothelin 1

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Women with hypertensive forms of pregnancy such as hemolysis–elevated liver enzymes–low platelet syndrome have increased circulating endothelin 1; however, the relationship between hypertension and endothelin 1 has not been studied. Using an animal model, we sought to determine whether there was an increased activation/dysfunction of endothelin 1, the effect of endothelin 1 receptor-A blockade on hypertension and other manifestations of hemolysis, elevated liver enzymes, and low platelets syndrome. On gestational day 12, timed-pregnant rats were infused with soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEndoglin; 4.7 and 7 µg/kg) via mini-osmotic pumps for 8 days. A subset of rats were treated with receptor-A antagonist (ABT-627, 5mg/kg) for 8 days. Rats with hemolysis-elevated liver enzymes-low platelet syndrome had significantly increased hypertension (P = .0001), circulating endothelin 1 (P = .03), and a significant 3.3- and 7.2-fold increase in preproendothelin messenger RNA (mRNA) expression in the placenta and liver (P = .01 and .04). Urinary protein:creatinine ratio was significantly increased in these animals (P = .0007), and circulating factors from these rats stimulated a significant increase in endothelial cell secretion of endothelin 1 (P = .001) in an in vitro assay. Blockade of the endothelin 1 receptor A significantly decreased hypertension (P = .001), circulating endothelin 1, and interleukin 17 (P = .004 and .003), placental preproendothelin mRNA expression (P = .016), and urinary protein:creatinine ratio (P = .007) in rats with hemolysis–elevated liver enzymes–low platelet syndrome. Blockade of the endothelin 1 receptor A significantly decreased hemolysis (P = .009), liver enzymes (P = .011), and significantly increased platelet levels (P = .03) and decreased circulating CD4+ and CD8+ T lymphocytes (P = .0004 and .0001) in rats infused with sFlt-1 and sEndoglin. These data support the hypothesis that endothelin 1 activation has a critical role in pathophysiology of as hemolysis–elevated liver enzymes–low platelet syndrome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Geary M. The HELLP syndrome. Br J Obstet Gynaecol. 1997;104(8):887–891.

    Article  CAS  PubMed  Google Scholar 

  2. Sibai B. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): Much ado about nothing? Am J Obstet Gynecol. 1990;162(2):311–316.

    Article  CAS  PubMed  Google Scholar 

  3. Abildgaard U, Heimdal K. Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): a review. Eur J Obstet Gynecol Reprod Biol. 2013;166(2):117–123.

    Article  CAS  PubMed  Google Scholar 

  4. Wallace K, Martin J Jr, Tam Tam K, et al. Seeking the mechanisms of action for corticosteroids in HELLP syndrome: SMASH study. Am J Obstet Gynecol. 2013;208(5):380.e1–e8.

    Article  CAS  Google Scholar 

  5. Strand S, Strand D, Seufert R, et al. Placenta-derived CD95 Ligand causes liver damage in hemolysis, elevated liver enzymes, and low platelet count syndrome. Gastroenterology. 2004;126(3):849–858.

    Article  CAS  PubMed  Google Scholar 

  6. Bussen S, Sutterlin M, Steck T. Plasma endothelin and big endothelin levels in women with severe preeclampsia or HELLP-syndrome. Arch Gynecol Obstet. 1999;262(3–4):113–119.

    Article  CAS  PubMed  Google Scholar 

  7. Tranquilli A, Landi B, Corradetti A, et al. Inflammatory cytokines patterns in the placenta of pregnancies complicated by HELLP (hemolysis, elevated liver enzyme, and low platelet) syndrome. Cytokine. 2007;40(2):82–88.

    Article  CAS  PubMed  Google Scholar 

  8. Lamarca B. Endothelial dysfunction. An important mediator in the pathophysiology of hypertension during pre-eclampsia. Minerva Ginecol. 2012;64(4):309–320.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Cai H, Griendling K, Harrison D. The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci. 2003;24(9):471–478.

    CAS  PubMed  Google Scholar 

  10. Wallace K, Novotny S, Heath J, et al. Hypertension in response to CD4+ T cells from reduced uterine perfusion pregnant rats is associated with activation of the endothelin-1 system. Am J Physiol Regul Integr Comp Physiol. 2012;303(2):R144–R149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Aggarwal P, Chandel N, Jain V, Jha V. The relationship between circulating endothelin-1, soluble fms-like tyrosine kinase-1 and soluble endoglin in preeclampsia. J Hum Hypertens. 2012;26(4):236–241.

    Article  CAS  PubMed  Google Scholar 

  12. Granger J, Abram S, Stec D, Chandler D, LaMarca B. Endothelin, the kidney and hypertension. Curr Hypertens Rep. 2006;8(4):298–303.

    Article  CAS  PubMed  Google Scholar 

  13. Lerman A, Kubo S, Tschumperlin L, Burnett JJ. Plasma endothelin concentrations in humans with end-stage heart failure and after heart-transplantation. J Am Coll Cardiol. 1992;20(4):849–853.

    Article  CAS  PubMed  Google Scholar 

  14. LaMarca B. The role of immune activation in contributing to vascular dysfunction and the pathophysiology of hypertension during preeclampsia. Minerva Ginecol. 2010;62(2):105–120.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. LaMarca B. Progress toward identifying potential markers for preeclampsia: a role of agonistic autoantibody to the angiotensin II type I receptor. Hypertension. 2010;55(2):236–237.

    Article  CAS  PubMed  Google Scholar 

  16. Lamarca B, Cornelius D, Wallace K. Elucidating immune mechanisms causing hypertension during pregnancy. Physiology. 2013;28(4):225–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li J, Lamarca B, Reckelhoff J. A model of preeclampsia in rats: the reduced uterine perfusion pressure (RUPP) model. Am J Physiol Heart Circ Physiol. 2012;303(1):H1–H8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tam Tam K, Lamarca B, Arany M, et al. Role of reactive oxygen species during hypertension in response to chronic antiangiogenic factor (sFlt-1) excess in pregnant rats. Am J Hypertens. 2011;24(1):110–113.

    Article  CAS  PubMed  Google Scholar 

  19. Benyo D, Smarason A, Redman C, Sims C, Conrad K. Expression of inflammatory cytokines in placentas from women with preeclampsia. J Clin Endocrinol Metab. 2001;86(6):2502–2512.

    Google Scholar 

  20. Kupferminc M, Peaceman A, Wigton T, Rehnberg K, Socol M. Tumor necrosis factor-alpha is elevated in plasma and amniotic fluid of patients with severe preeclampsia. Am J Obstet Gynecol. 1994;170(6):1752–1757.

    Article  CAS  PubMed  Google Scholar 

  21. Wallace K, Morris R, Kyle P, et al. Hypertension, inflammation and T lymphocytes are increased in a rat model of HELLP syndrome. Hypertens Pregnancy. 2014;33(1):41–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006;12(6):642–649.

    Article  CAS  PubMed  Google Scholar 

  23. Maynard S, Min J, Merchan J, et al. Excess placental soluble fmslike tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111(5):649–658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. LaMarca B, Cockrell K, Sullivan E, Bennett W, Granger J. Role of endothelin in mediating tumor necrosis factor-induced hypertension in pregnant rats. Hypertension. 2005;46(1):82–86.

    Article  CAS  PubMed  Google Scholar 

  25. Amaral L, Kiprono L, Cornelius D, et al. Progesterone supplementation attenuates hypertension and the autoantibody to the angiotensin II type 1 receptor in response to elevated interleukin-6 during pregnancy. Am J Obstet Gynecol. 2014;211(2):158.e1–e6.

    Article  CAS  Google Scholar 

  26. Wallace K, Cornelius D, Scott J, et al. CD4+ T cells are important mediators of oxidative stress that cause hypertension in response to placental ischemia. Hypertension. 2014;64(5):1151–1158.

    Article  CAS  PubMed  Google Scholar 

  27. Wallace K, Richards S, Dhillion P, et al. CD4+ T Helper cells stimulated in response to placental ischemia mediate hypertension during pregnancy. Hypertension. 2011;57(5):949–955.

    Article  CAS  PubMed  Google Scholar 

  28. Wallace K, Chatman K, Porter J, et al. Endothelin-1 is elevated in plasma and explants from patients suffering with uterine leiomyomas. Reprod Sci. 2014;21(9):1196–1205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Novotny S, Wallace K, Herse F, et al. CD4+ T cells play a critical role in mediating hypertension in response to placental ischemia. J Hypertens. 2013;2:1–6.

    Google Scholar 

  30. George E, Cockrell K, Adair T, Granger J. Regulation of sFlt-1 and VEGF secretion by adenosine under hypoxic conditions in rat placental villous explants. Am J Physiol Regul Integr Comp Physiol. 2010;299(6):R1629–R1633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Roberts J, Edep M, Goldfien A, Taylor R. Sera from preeclamptic women specifically activate human umblical vein enodothelial cells in vitro: morphological and biochemical evidence. Am J Reprod Immunol. 1992;27(3–4):101–108.

    Article  CAS  PubMed  Google Scholar 

  32. Roberts L, LaMarca B, Fournier L, Bain J, Cockrell K, Granger J. Enhanced endothelin synthesis by endothelial cells exposed to sera from pregnant rats with decreased uterine perfusion. Hypertension. 2006;47(3):615–618.

    Article  CAS  PubMed  Google Scholar 

  33. Pollock D, Opgenorth T. ETA receptor mediated responses to ET-1 in the rat kidney. Br J Pharmacol. 1994;111(3):729–732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Parrish M, Murphy S, Rutland S, et al. The effect of immune factors, tumor necrosis factor-alpha, and agonistic autoantibodies to the angiotensin II type I receptor on soluble fms-like tyrosine-1 and soluble endoglin production in response to hypertension during pregnancy. Am J Hypertens. 2010;23(8):911–916.

    Article  CAS  PubMed  Google Scholar 

  35. Tanaka K, Yoshioka K, Tatsumi K, Kimura S, Kasuya Y. Endothelin regulates function of IL-17 producing T cell subset. Life Sci. 2014;118(2):244–247.

    Article  CAS  PubMed  Google Scholar 

  36. Cornelius D, Hogg J, Scott J, et al. Administration of interleukin-17 soluble receptor C suppresses TH17 cells, oxidative stress and hypertension in response to placental ischemia during pregnancy. Hypertension. 2013;62(6):1068–1073.

    Article  CAS  PubMed  Google Scholar 

  37. Cornelius D, Wallace K, Kiprono L, Dhillion P, Moseley J, Lamarca B. Endothelin-1 is not a mechanism of IL-17 induced hypertension during pregnancy. Med J Obstet Gynecol. 2013;1(1):1–10.

    Article  Google Scholar 

  38. Dhillion P, Wallace K, Scott J, et al. IL-17 mediated oxidative stress is an important stimulator of AT1-AA and hypertension during pregnancy. Am J Physiol Regul Integr Comp Physiol. 2012;303(4):R353–R358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Murphy S, LaMarca B, Cockrell K, Granger J. Role of Endothelin in Mediating Soluble fms-Like Tyrosine Kinase 1 Induced Hypertension in Pregnant Rats. Hypertension. 2010;55(2):394–398.

    Article  CAS  PubMed  Google Scholar 

  40. Halim A, Kanayama N, Maehara K, Takahashi M, Terao T. HELLP syndrome-like biochemical parameters obtained with endothelin-1 injections in rabbits. Gynecol Obstet Invest. 1993;35(4):193–198.

    Article  CAS  PubMed  Google Scholar 

  41. Bahde R, Kapoor S, Viswanathan P, Spiegel H, Gupta S. Endothelin-1 receptor A blocker Darusentan decreases hepatic changes and improves liver repopulation after cell transplantation in rats. Hepatology. 2014;59(3):1107–1117.

    Article  CAS  PubMed  Google Scholar 

  42. Shchekotova A, Shchekotov V, Bulatova I, Roitman A. Diagnostic efficiency of laboratory tests determining the functional status of the endothelium in patients with chronic diffuse liver diseases. Klin Lab Diagn. 2009;(10):24–26.

    Google Scholar 

  43. Feng Z, Xu X, Wu L, Wu J, Zhu S, Zheng S. Downregulation of endothelin-1 by somatostatin improves liver function of recipients undergoing adult-to-adult living donor liver transplantation. Chin Med J. 2010;123(15):1961–1966.

    CAS  PubMed  Google Scholar 

  44. Jeremy J, Shukla N, Wan S, Murphy G, Angelini G, Yim A, et al. The pathobiology of endothelin-1 in vein graft disease: Are ETA receptor antagonists the solution to prevent vein graft failure? Curr Vasc Pharmacol. 2005;3(4):315–323.

    Article  CAS  PubMed  Google Scholar 

  45. Jagroop I, Daskalopoulou S, Mikhailidis D. Endothelin-1 and human platelets. Curr Vasc Pharmacol. 2005;3(4):393–399.

    Article  CAS  PubMed  Google Scholar 

  46. Helset E, Lindal S, Olsen R, Myklebust R, Jorgensen L. Endothelin-1 causes sequential trapping of platelets and neutrophils in pulmonary microcirculation in rats. Am J Physiol. 1996;271(14 pt 1):L538–L546.

    CAS  PubMed  Google Scholar 

  47. Amraoui F, Spijkers L, Hassani Lahsionoui H, et al. SFlt-1 elevates blood pressure by augmenting endothelin-1 mediated vasoconstriction in mice. PLos One. 2014;9(3):e91897.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Li F, Hagaman J, Kim H, et al. eNOS deficiency acts through endothelin to aggravate sFlt-1 induced pre-eclampsia like phenotype. J Am Soc Nephrol. 2012;23(4):652–660.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Shen F, Wei J, Snowise S, et al. Trophoblast debris extruded from preeclamptic placentae activates endothelial cells: a mechanism by which the placenta communicates with the maternal endothelium. Placenta. 2014;35(10):839–847.

    Article  CAS  PubMed  Google Scholar 

  50. Lau S, Barrett C, Guild S, Chamley L. Necrotic trophoblast decris increases blood pressure during pregnancy. J Reprod Immunol. 2013;97(2):175–182.

    Article  PubMed  Google Scholar 

  51. LaMarca B, Bennett W, Alexander B, Cockrell K, Granger J. Hypertension produced by reductions in uterine perfusion in the pregnant rat: role of tumor necrosis factor-alpha. Hypertension. 2005;46(4):1022–1025.

    Article  CAS  PubMed  Google Scholar 

  52. Sedeek M, Gilbert J, LaMarca B, et al. Role of reactive oxygen species in hypertension produced by reduced uterine perfusion in pregnant rats. Am J Hypertens. 2008;21(10):1152–1156.

    Article  CAS  PubMed  Google Scholar 

  53. Sanchez-Aranguren L, Prada C, Riano-Medina C, Lopez M. Endothelial dysfunction and preeclampsia: a role of oxidative stress. Front Physiol. 2014;5:1–11.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Mississippi Medical Center, 2500 N. State Street, 39216, Jackson, MS, USA

    Rachael Morris MD, Shauna-Kay Spencer MS, Al’shondra Harris MS, Michelle Y. Owens MD & Kedra Wallace PhD

  2. Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA

    Patrick B. Kyle PhD

  3. Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS, USA

    Jan Michael Williams PhD

Authors
  1. Rachael Morris MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shauna-Kay Spencer MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick B. Kyle PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan Michael Williams PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Al’shondra Harris MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michelle Y. Owens MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kedra Wallace PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kedra Wallace PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Morris, R., Spencer, SK., Kyle, P.B. et al. Hypertension in an Animal Model of HELLP Syndrome is Associated With Activation of Endothelin 1. Reprod. Sci. 23, 42–50 (2016). https://doi.org/10.1177/1933719115592707

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719115592707

Keywords

Search

Navigation