PDF herunterladen
CC BY 4.0 · Rev Bras Ginecol Obstet 2022; 44(02): 125-132
DOI: 10.1055/s-0042-1742317
Original Article
High Risk Pregnancy

Expression of Endothelin-1 and Endothelial Nitric Oxide Synthase in Normal and Preeclamptic Placentae

Expressão de endotelina-1 e de óxido nítrico sintase endotelial em placentas normais e pré-eclâmpticas
Aung Khaing 
1   Department of Physiology, University of Medicine 2, Yangon, The Republic of the Union of Myanmar
,
Aye Thet Swe 
1   Department of Physiology, University of Medicine 2, Yangon, The Republic of the Union of Myanmar
,
Cho Lwin Aung 
1   Department of Physiology, University of Medicine 2, Yangon, The Republic of the Union of Myanmar
,
Mya Mya Thwin 
2   Physiology Unit, Universiti Sultan Zanial Abidin, Kuala Terengganu,Terengganu, Malaysia
,
Mya Thanda Sein 
1   Department of Physiology, University of Medicine 2, Yangon, The Republic of the Union of Myanmar
› Institutsangaben
› Weitere Informationen
   Lizenzen und Reprints

Abstract

Objective To investigate the expression of endothelin-1 (ET-1) and endothelial nitric oxide (NO) synthase (eNOS) in normal and preeclamptic (PE) placentae.

Methods The present cross-sectional analytical study was performed in normal and PE primigravidae (n = 10 in each group) who were admitted to the North Okkalapa General and Teaching Hospital from February 2019 to February 2020. Serum samples were collected immediately before delivery, and placental tissues were collected immediately after emergency or elective cesarean section. The expression of placental eNOS was measured by western blot, and the levels of ET-1 in placental tissue homogenates and in the serum were measured by enzyme-linked immunosorbent assay (ELISA).

Results The PE group had significantly higher serum levels of ET-1 (median: 116.56 pg/mL; IQR: 89.14–159.62 pg/mL) than the normal group (median: 60.02 pg/mL; IQR: 50.89–94.37 pg/mL) (p < 0.05). However, statistically significant differences were not observed in the levels of ET-1 in placental tissue homogenates between normal and PE placentae (median: 0.007 pg/µg of total protein; IQR: 0.002–0.0123 pg/µg of total protein; and median: 0.005 pg/µg of total protein; IQR: 0.003–0.016 pg/µg of total protein respectively). The median and IQR values of relative placental eNOS expression were significantly higher in the PE group than in the normal group (p < 0.05). The serum levels of ET-1 level were not significantly correlated with placental ET-1 expression, and neither there was a significant correlation between placental ET-1 and eNOS expression in any of the groups.

Conclusion The serum levels of ET-1 were significantly higher in PE pregnant women compared with normal pregnant women, while the ET-1 levels of placental tissue homogenates were not significantly different. Serum ET-1 rather than placental ET-1 might play a major role in the pathogenesis of PE.

Resumo

Objetivo Investigar a expressão da endotelina-1 (ET-1) e da óxido nítrico sintase endotelial (endothelial nitric oxide synthase, eNOS, em inglês) em placentas normais e com pré-eclâmpsia (PE).

Métodos Este estudo transversal e analítico foi realizado em primigestas normais e com PE (n = 10 em cada grupo) internadas no Hospital Geral e das Clínicas de North Okkalapa entre fevereiro de 2019 e fevereiro de 2020. Amostras de soro foram coletadas imediatamente antes do parto, e os tecidos placentários foram coletados imediatamente após cesariana de emergência ou eletiva. A expressão da eNOS da placenta foi medida por western blot, e os níveis de ET-1 nos homogenatos de tecidos placentários ET-1 e no soro foram medidos por ensaio de imunoabsorção enzimática.

Resultados O grupo com PE apresentou níveis séricos de ET-1 significativamente mais altos (mediana: 116,56 pg/mL; IIQ: 89,14–159,62 pg/mL) do que o grupo normal (mediana: 60,02 pg/mL; IIQ: 50,89–94,37 pg/mL) (p < 0,05). No entanto, não foi observada diferença significativa no nível ET-1 dos homogenatos de tecidos placentários entre placentas normais e com PE (mediana: 0,007 pg/µg de proteína total; IIQ: 0,002–0,0123 pg/µg de proteína total; e mediana: 0,005 pg/µg de proteína total; IIQ: 0,003–0,016 pg/µg de proteína total, respectivamente). Os valores da mediana e do IIQ da expressão relativa da eNOS placentária foram significativamente maiores no grupo com PE do que no grupo normal (p < 0,05). O nível sérico de ET-1 não estava significativamente correlacionado com a expressão placentária de ET-1, e tampouco houve correlação significativa entre as expressões placentária de ET-1 e de eNOS em nenhum dos grupos.

Conclusão Os níveis séricos de ET-1 foram significativamente maiores em gestantes com PE em comparação com gestantes normais, ao passo que os níveis de ET-1 dos homogenatos de tecidos placentários não foram significativamente diferentes. A ET-1 sérica, em vez da ET-1 placentária, pode desempenhar um papel importante na patogênese da EP.

Keywords

endothelial nitric oxide synthase - endothelin-1 - placenta - preeclampsia

Palavras-chave

óxido nítrico sintase endotelial - endotelina-1 - placenta - pré-eclâmpsia

Contributors

All authors were involved in the design and interpretation of the analyses, contributed to the writing of the manuscript, and read and approved the final manuscript.




Publikationsverlauf

Eingereicht: 13. Januar 2021

Angenommen: 11. November 2021

Artikel online veröffentlicht:
25. Februar 2022

© 2022. Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Revinter Publicações Ltda.
Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

 

  • References

  • 1 Bourque SL, Davidge ST, Adams MA. The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives. Am J Physiol Regul Integr Comp Physiol 2011; 300 (06) R1288-R1295 DOI: 10.1152/ajpregu.00397.2010.
    CrossrefPubMedGoogle Scholar
  • 2 Palmer RM, Rees DD, Ashton DS, Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun 1988; 153 (03) 1251-1256 DOI: 10.1016/s0006-291x(88)81362-7.
    CrossrefPubMedGoogle Scholar
  • 3 Baker PN, Davidge ST, Roberts JM. Plasma from women with preeclampsia increases endothelial cell nitric oxide production. Hypertension 1995; 26 (02) 244-248 DOI: 10.1161/01.hyp.26.2.244.
    CrossrefPubMedGoogle Scholar
  • 4 Smith-Jackson K, Hentschke MR, Poli-de-Figueiredo CE, Pinheiro-da-Costa BE, Kurlak LO, Pipkin FB. et al. Placental expression of eNOS, iNOS and the major protein components of caveolae in women with pre-eclampsia. Placenta 2015; 36 (05) 607-610 DOI: 10.1016/j.placenta.2015.02.001.
    CrossrefPubMedGoogle Scholar
  • 5 Wang Y, Gu Y, Zhang Y, Lewis DF. Evidence of endothelial dysfunction in preeclampsia: decreased endothelial nitric oxide synthase expression is associated with increased cell permeability in endothelial cells from preeclampsia. Am J Obstet Gynecol 2004; 190 (03) 817-824 DOI: 10.1016/j.ajog.2003.09.049.
    CrossrefPubMedGoogle Scholar
  • 6 Ranta V, Viinikka L, Halmesmäki E, Ylikorkala O. Nitric oxide production with preeclampsia. Obstet Gynecol 1999; 93 (03) 442-445 DOI: 10.1016/s0029-7844(98)00465-7.
    CrossrefPubMedGoogle Scholar
  • 7 Nishikawa S, Miyamoto A, Yamamoto H, Ohshika H, Kudo R. The relationship between serum nitrate and endothelin-1 concentrations in preeclampsia. Life Sci 2000; 67 (12) 1447-1454 DOI: 10.1016/s0024-3205(00)00736-0.
    CrossrefPubMedGoogle Scholar
  • 8 Bernardi FC, Vuolo F, Petronilho F, Michels M, Ritter C, Dal-Pizzol F. Plasma nitric oxide, endothelin-1, arginase and superoxide dismutase in the plasma and placentae from preeclamptic patients. An Acad Bras Cienc 2015; 87 (02) 713-719 DOI: 10.1590/0001-3765201520140069.
    CrossrefPubMedGoogle Scholar
  • 9 Verdonk K, Saleh L, Lankhorst S, Smilde JE, van Ingen MM, Garrelds IM. et al. Association studies suggest a key role for endothelin-1 in the pathogenesis of preeclampsia and the accompanying renin-angiotensin-aldosterone system suppression. Hypertension 2015; 65 (06) 1316-1323 DOI: 10.1161/HYPERTENSIONAHA.115.05267.
    CrossrefPubMedGoogle Scholar
  • 10 George EM, Palei AC, Granger JP. Endothelin as a final common pathway in the pathophysiology of preeclampsia: therapeutic implications. Curr Opin Nephrol Hypertens 2012; 21 (02) 157-162 DOI: 10.1097/MNH.0b013e328350094b.
    CrossrefPubMedGoogle Scholar
  • 11 Zeng Y, Li M, Chen Y, Wang S. Homocysteine, endothelin-1 and nitric oxide in patients with hypertensive disorders complicating pregnancy. Int J Clin Exp Pathol 2015; 8 (11) 15275-15279
    PubMedGoogle Scholar
  • 12 Napolitano M, Miceli F, Calce A, Vacca A, Gulino A, Apa R. et al. Expression and relationship between endothelin-1 messenger ribonucleic acid (mRNA) and inducible/endothelial nitric oxide synthase mRNA isoforms from normal and preeclamptic placentas. J Clin Endocrinol Metab 2000; 85 (06) 2318-2323 DOI: 10.1210/jcem.85.6.6623.
    CrossrefPubMedGoogle Scholar
  • 13 Irtegun S, Tekin MA, Alpayci R. Increased expression of e-cadherin, endothelin-1, and CD68 in preeclamptic placentas. Erciyes Med J 2016; 38 (04) 149-152 DOI: 10.5152/etd.2016.0090.
    CrossrefPubMedGoogle Scholar
  • 14 Dieber-Rotheneder M, Beganovic S, Desoye G, Lang U, Cervar-Zivkovic M. Complex expression changes of the placental endothelin system in early and late onset preeclampsia, fetal growth restriction and gestational diabetes. Life Sci 2012; 91 (13-14): 710-715 DOI: 10.1016/j.lfs.2012.04.040.
    CrossrefPubMedGoogle Scholar
  • 15 Benigni A, Orisio S, Gaspari F, Frusca T, Amuso G, Remuzzi G. Evidence against a pathogenetic role for endothelin in pre-eclampsia. Br J Obstet Gynaecol 1992; 99 (10) 798-802 DOI: 10.1111/j.1471-0528.1992.tb14409.x.
    CrossrefPubMedGoogle Scholar
  • 16 Faxén M, Nasiell J, Lunell NO, Blanck A. Differences in mRNA expression of endothelin-1, c-fos and c-jun in placentas from normal pregnancies and pregnancies complicated with preeclampsia and/or intrauterine growth retardation. Gynecol Obstet Invest 1997; 44 (02) 93-96 DOI: 10.1159/000291494.
    CrossrefPubMedGoogle Scholar
  • 17 Tsukahara H, Ende H, Magazine HI, Bahou WF, Goligorsky MS. Molecular and functional characterization of the non-isopeptide-selective ETB receptor in endothelial cells. Receptor coupling to nitric oxide synthase. J Biol Chem 1994; 269 (34) 21778-21785
    CrossrefPubMedGoogle Scholar
  • 18 Liu S, Premont RT, Kontos CD, Huang J, Rockey DC. Endothelin-1 activates endothelial cell nitric-oxide synthase via heterotrimeric G-protein betagamma subunit signaling to protein jinase B/Akt. J Biol Chem 2003; 278 (50) 49929-49935 DOI: 10.1074/jbc.M306930200.
    CrossrefPubMedGoogle Scholar
  • 19 Brown MA, Magee LA, Kenny LC, Karumanchi SA, McCarthy FP, Saito S. et al; International Society for the Study of Hypertension in Pregnancy (ISSHP). The hypertensive disorders of pregnancy: ISSHP classification, diagnosis & management recommendations for international practice. Pregnancy Hypertens 2018; 13: 291-310
    CrossrefPubMedGoogle Scholar
  • 20 Taddei S, Virdis A, Ghiadoni L, Salvetti G, Bernini G, Magagna A. et al. Age-related reduction of NO availability and oxidative stress in humans. Hypertension 2001; 38 (02) 274-279 DOI: 10.1161/01.HYP.38.2.274.
    CrossrefPubMedGoogle Scholar
  • 21 Choi JW, Im MW, Pai SH. Nitric oxide production increases during normal pregnancy and decreases in preeclampsia. Ann Clin Lab Sci 2002; 32 (03) 257-263
    PubMedGoogle Scholar
  • 22 Brosens I. A study of the spiral arteries of the decidua basalis in normotensive and hypertensive pregnancies. J Obstet Gynaecol Br Commonw 1964; 71: 222-230 DOI: 10.1111/j.1471-0528.1964.tb04270.x.
    CrossrefPubMedGoogle Scholar
  • 23 Sánchez-Aranguren LC, Prada CE, Riaño-Medina CE, Lopez M. Endothelial dysfunction and preeclampsia: role of oxidative stress. Front Physiol 2014; 5: 372 DOI: 10.3389/fphys.2014.00372.
    CrossrefPubMedGoogle Scholar
  • 24 Maynard S, Epstein FH, Karumanchi SA. Preeclampsia and angiogenic imbalance. Annu Rev Med 2008; 59: 61-78 DOI: 10.1146/annurev.med.59.110106.214058.
    CrossrefPubMedGoogle Scholar
  • 25 Seki H. Balance of antiangiogenic and angiogenic factors in the context of the etiology of preeclampsia. Acta Obstet Gynecol Scand 2014; 93 (10) 959-964 DOI: 10.1111/aogs.12473.
    CrossrefPubMedGoogle Scholar
  • 26 Aggarwal PK, 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 (04) 236-241 DOI: 10.1038/jhh.2011.29.
    CrossrefPubMedGoogle Scholar
  • 27 Kupferminc MJ, Peaceman AM, Wigton TR, Rehnberg KA, Socol ML. Tumor necrosis factor-alpha is elevated in plasma and amniotic fluid of patients with severe preeclampsia. Am J Obstet Gynecol 1994; 170 (06) 1752-1757 , discussion 1757–1759
    CrossrefPubMedGoogle Scholar
  • 28 LaMarca BD, Gilbert J, Granger JP. Recent progress toward the understanding of the pathophysiology of hypertension during preeclampsia. Hypertension 2008; 51 (04) 982-988 DOI: 10.1161/HYPERTENSIONAHA.107.108837.
    CrossrefPubMedGoogle Scholar
  • 29 Rajagopalan S, Laursen JB, Borthayre A, Kurz S, Keiser J, Haleen S. et al. Role for endothelin-1 in angiotensin II-mediated hypertension. Hypertension 1997; 30 (1 Pt 1): 29-34 DOI: 10.1161/01.hyp.30.1.29.
    CrossrefPubMedGoogle Scholar
  • 30 Myatt L, Eis AL, Brockman DE, Greer IA, Lyall F. Endothelial nitric oxide synthase in placental villous tissue from normal, pre-eclamptic and intrauterine growth restricted pregnancies. Hum Reprod 1997; 12 (01) 167-172 DOI: 10.1093/humrep/12.1.167.
    CrossrefPubMedGoogle Scholar
  • 31 Ghabour MS, Eis AL, Brockman DE, Pollock JS, Myatt L. Immunohistochemical characterization of placental nitric oxide synthase expression in preeclampsia. Am J Obstet Gynecol 1995; 173 (3 Pt 1): 687-694 DOI: 10.1016/0002-9378(95)90324-0.
    CrossrefPubMedGoogle Scholar
  • 32 Corthorn J, Germain AA, Chacón C, Rey S, Soto GX, Figueroa CD. et al. Expression of kallikrein, bradykinin b2 receptor, and endothelial nitric oxide synthase in placenta in normal gestation, preeclampsia, and placenta accreta. Endocrine 2006; 29 (03) 491-499 DOI: 10.1385/ENDO:29:3:491.
    CrossrefPubMedGoogle Scholar
  • 33 Weng YH, Kuo CY, Chiu YW, Kuo ML, Liao SL. Alteration of nitric oxide gas on gene expression of endothelin-1 and endothelial nitric oxide synthase by a time- and dose-dependent manner in human endothelial cells. Chin J Physiol 2009; 52 (02) 59-64
    PubMedGoogle Scholar
  • 34 Kuchan MJ, Frangos JA. Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Am J Physiol 1993; 264 (1 Pt 2): H150-H156 DOI: 10.1152/ajpheart.1993.264.1.H150.
    CrossrefPubMedGoogle Scholar
  • 35 Goligorsky MS, Tsukahara H, Magazine H, Andersen TT, Malik AB, Bahou WF. Termination of endothelin signaling: role of nitric oxide. J Cell Physiol 1994; 158 (03) 485-494 DOI: 10.1002/jcp.1041580313.
    CrossrefPubMedGoogle Scholar