Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Testosterone attenuates hypoxia-induced hypertension by affecting NRF1-mediated transcriptional regulation of ET-1 and ACE

Hypertension Research volume 44, pages 1395–1405 (2021)Cite this article

Abstract

Hypertension induced by hypoxia at high altitude is one of the typical symptoms of high-altitude reactions (HARs). Emerging evidence indicates that endothelial abnormalities, including increases in angiotensin-2 (Ang-2) and endothelin-1 (ET-1), are closely associated with hypertension. Thus, low blood oxygen-induced endothelial dysfunction through acceleration of Ang-2 and ET-1 synthesis may alleviate HARs. In this study, we investigated the effects of hypoxia on rat blood pressure (BP) and endothelial injury. We found that BP increased by 10 mmHg after treatment with 10% O2 (~5500 m above sea level) for 24 h. Consistently, serum Ang-2 and ET-1 levels were increased along with decreases in NO levels. In endothelial cells, angiotensin-1-converting enzyme (ACE) and ET-1 expression levels were upregulated. Interestingly, nuclear respiratory factor 1 (NRF1) levels were also upregulated, consistent with the changes in ACE and ET-1 levels. We further demonstrated that NRF1 transcriptionally activated ACE and ET-1 by directly binding to their promoter regions, suggesting that the endothelial cell dysfunction induced by hypoxia was due to NRF1-dependent upregulation of ACE and ET-1. Surprisingly, testosterone supplementation showed significant protective effects on BP, while castration induced even higher BPs in rats exposed to hypoxia. We further showed that physiological testosterone repressed NRF1 expression in vivo and in vitro and thereby reduced Ang-2 and ET-1 levels, which was dependent on hypoxia. In summary, we have identified that physiological testosterone protects against hypoxia-induced hypertension through inhibition of NRF1, which transcriptionally regulates ACE and ET-1 expression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Disease EC, Tomelleri A, Cavalli G, Berti A, Dagna L. Erdheim-Chester disease. Eur J Intern Med. 2015;26:223–9.

    Article  CAS  Google Scholar 

  2. Kropfl JM, Kammerer T, Faihs V, Gruber HJ, Stutz J, Rehm M, et al. Acute exercise in hypobaric hypoxia attenuates endothelial shedding in subjects unacclimatized to high altitudes. Front Physiol. 2019;10:1632.

    Article  PubMed  Google Scholar 

  3. Wolfel EE, Selland MA, Mazzeo RS, Reeves JT. Systemic hypertension at 4,300 m is related to sympathoadrenal activity. J Appl Physiol. 1994;76:1643–50.

    Article  CAS  PubMed  Google Scholar 

  4. Mazzeo RS, Carroll JD, Butterfield GE, Braun B, Rock PB, Wolfel EE, et al. Catecholamine responses to alpha-adrenergic blockade during exercise in women acutely exposed to altitude. J Appl Physiol. 2001;90:121–6.

    Article  CAS  PubMed  Google Scholar 

  5. Bilo G, Caldara G, Styczkiewicz K, Revera M, Lombardi C, Giglio A, et al. Effects of selective and nonselective beta-blockade on 24-h ambulatory blood pressure under hypobaric hypoxia at altitude. J Hypertens. 2011;29:380–7.

    Article  CAS  PubMed  Google Scholar 

  6. Grocott M. Commentary. J Intensive Care Soc. 2012;13:204–5.

    Article  Google Scholar 

  7. Santos RA, Ferreira AJ, Ac SES. Recent advances in the angiotensin-converting enzyme 2-angiotensin(1-7)-Mas axis. Exp Physiol. 2008;93:519–27.

    Article  CAS  PubMed  Google Scholar 

  8. Narvaez-Guerra O, Herrera-Enriquez K, Medina-Lezama J, Chirinos JA. Systemic hypertension at high altitude. Hypertension. 2018;72:567–78.

    Article  CAS  PubMed  Google Scholar 

  9. Wood KC, Liu VB, Noguchi A, Wang XD, Raghavachari N, Gladwin MT. Blood cell versus vascular endothelial cell contributions to nitrite homeostasis and blood pressure regulation. Free Radic Biol Med. 2008;45:S118–9.

    Google Scholar 

  10. Rickard AJ, Morgan J, Chrissobolis SB, Miller AA, Sobey CG, Young MJ. Endothelial cell mineralocorticoid receptors regulate deoxycorticosterone/salt-mediated cardiac remodeling and vascular reactivity, but not blood pressure. Hypertension. 2014;63:E160

    Article  CAS  Google Scholar 

  11. Amiri F, Paradis P, Reudelhuber TL, Schiffrin EL. Vascular inflammation in absence of blood pressure elevation in transgenic murine model overexpressing endothelin-1 in endothelial cells. J Hypertens. 2008;26:1102–9.

    Article  CAS  PubMed  Google Scholar 

  12. Chuaiphichai S, Rashbrook VS, Hale AB, Trelfa L, Mcneill E, Lygate CA, et al. Deficiency in endothelial cell tetrahydrobiopterin increases resistance vascular remodelling, blood pressure, and susceptibility to aortic abdominal aneurysm in response to angiotensin II. Cardiovasc Res. 2018;114:S90.

    Article  Google Scholar 

  13. Ten VS, Pinsky DJ. Endothelial response to hypoxia: physiologic adaptation and pathologic dysfunction. Curr Opin Crit Care. 2002;8:242–50.

    Article  PubMed  Google Scholar 

  14. Baldea I, Teacoe I, Olteanu DE, Vaida-Voievod C, Clichici A, Sirbu A, et al. Effects of different hypoxia degrees on endothelial cell cultures—time course study. Mech Ageing Dev. 2018;172:45–50.

    Article  CAS  PubMed  Google Scholar 

  15. Michiels C, Arnould T, Remacle J. Endothelial cell responses to hypoxia: initiation of a cascade of cellular interactions. Biochim Biophys Acta. 2000;1497:1–10.

    Article  CAS  PubMed  Google Scholar 

  16. Adam T, Makaula S, Essop MF. Nuclear respiratory factor 1: a novel inhibitor of the human gene promoter of the cardiac isoform of acetyl-coa carboxylase. Cardiovasc Drug Ther. 2006;20:396.

    Google Scholar 

  17. Scarpulla R. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev. 2008;88:611–38.

    Article  CAS  PubMed  Google Scholar 

  18. Tiranti V, Rossi E, Rocchi M, Didonato S, Zuffardi O, Zeviani M. The gene (NFE2L1) for human NRF-1, an activator involved in nuclear-mitochondrial interactions, maps to 7q32. Genomics. 1995;27:555–7.

  19. Scarpulla RC. Nuclear respiratory factors and the pathways of nuclear-mitochondrial interaction. Trends Cardiovas Med. 1996;6:39–45.

    Article  CAS  Google Scholar 

  20. Jun-Ichi S, Natsuki K, Yoji Y. Pathway analysis of ChIP-seq-based NRF1 target genes suggests a logical hypothesis of their involvement in the pathogenesis of neurodegenerative diseases. Gene Regul Syst Biol. 2013;7:139–52.

    Google Scholar 

  21. Wang D, Zhang J, Lu Y, Luo Q, Zhu L. Nuclear respiratory factor-1 (NRF-1) regulated hypoxia-inducible factor-1alpha (HIF-1alpha) under hypoxia in HEK293T. IUBMB Life. 2016;68:748–55.

    Article  CAS  PubMed  Google Scholar 

  22. Wang X, Jin L, Jiang S, Wang D, Lu Y, Zhu L. Transcription regulation of NRF1 on StAR reduces testosterone synthesis in hypoxemic murine. J Steroid Biochem Mol Biol. 2019;191:105370.

    Article  CAS  PubMed  Google Scholar 

  23. Webb CM, Mcneill JG, Hayward CS, Zeigler D, De, Collins P. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation. 1999;100:1690–6.

    Article  CAS  PubMed  Google Scholar 

  24. Lauro FV, Hector L, Carlos CH, Olga MOG, Tomas MC, Guillermo CR. Synthesis and evaluation of the cardiovascular effects of two, membrane impermeant, macromolecular complexes of dextran-testosterone. Steroids. 2002;67:611–9.

    Article  Google Scholar 

  25. Villar IC, Francis S, Webb A, Hobbs AJ, Ahluwalia A. Novel aspects of endothelium-dependent regulation of vascular tone. Kidney Int. 2006;70:840–53.

    Article  CAS  PubMed  Google Scholar 

  26. Montalcini T, Gorgone G, Gazzaruso C, Sesti G, Perticone F, Pujia A. Endogenous testosterone and endothelial function in postmenopausal women. Coron Artery Dis. 2007;18:9.

    Article  PubMed  Google Scholar 

  27. Suzuki T, Nakamura Y, Moriya T, Sasano H. Effects of steroid hormones on vascular functions. Microsc Res Tech. 2010;60:76.

    Article  CAS  Google Scholar 

  28. Yildiz O, Seyrek M. Vasodilating mechanisms of testosterone. Exp Clin Endocrinol Diabetes. 2007;115:1–6.

    Article  CAS  PubMed  Google Scholar 

  29. Wang X, Pan L, Zou Z, Wang D, Lu Y, Dong Z, et al. Hypoxia reduces testosterone synthesis in mouse Leydig cells by inhibiting NRF1-activated StAR expression. Oncotarget. 2017;8:16401–13.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Wang X, Zou Z, Yang Z, Jiang S, Lu Y, Wang D, et al. HIF 1 inhibits StAR transcription and testosterone synthesis in murine Leydig cells. J Mol Endocrinol. 2018;62:1–12.

  31. Wang X, Huang L, Jiang S, Cheng K, Wang D, Luo Q, et al. Testosterone attenuates pulmonary epithelial inflammation in male rats of COPD model through preventing NRF1-derived NF-kappaB signaling. J Mol Cell Biol. 2021;13:128–140.

  32. Hotta Y, Kataoka T, Kimura K. Testosterone deficiency and endothelial dysfunction: nitric oxide, asymmetric dimethylarginine, and endothelial progenitor cells. Sex Med Rev. 2019;7:661–8.

    Article  PubMed  Google Scholar 

  33. Marin R, Escrig A, Abreu P, Mas M. Androgen-dependent nitric oxide release in rat penis correlates with levels of constitutive nitric oxide synthase isoenzymes. Biol Reprod. 1999;61:1012–6.

    Article  CAS  PubMed  Google Scholar 

  34. Elesber AA, Solomon H, Lennon RJ, Mathew V, Prasad A, Pumper G, et al. Coronary endothelial dysfunction is associated with erectile dysfunction and elevated asymmetric dimethylarginine in patients with early atherosclerosis. Eur Heart J. 2006;27:824–31.

    Article  CAS  PubMed  Google Scholar 

  35. Kumanov P, Tomova A, Kirilov G, Dakovska L, Schinkov A. Increased plasma endothelin levels in patients with male hypogonadism. Andrologia. 2002;34:29–33.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang HL, Yue ZP, Zhang L, Yang ZQ, Geng S, Wang K, et al. Expression and regulation of angiopoietins and their receptor Tie-2 in sika deer antler. Anim Cells Syst. 2017;21:177–84.

    Article  CAS  Google Scholar 

  37. Gassmann M, Cowburn A, Gu H, Li J, Rodriguez M, Babicheva A, et al. Hypoxia-induced pulmonary hypertension—utilizing experiments of nature. Br J Pharm. 2021;178:121–31.

    Article  CAS  Google Scholar 

  38. Nanduri J, Peng YJ, Yuan G, Kumar GK, Prabhakar NR. Hypoxia-inducible factors and hypertension: lessons from sleep apnea syndrome. J Mol Med. 2015;93:473–80.

    Article  CAS  PubMed  Google Scholar 

  39. Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J. 2008;32:1371–85.

    Article  CAS  PubMed  Google Scholar 

  40. Yamashita K, Discher DJ, Hu J, Bishopric NH, Webster KA. Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. J Biol Chem. 2001;276:12645–53.

    Article  CAS  PubMed  Google Scholar 

  41. Zhang R, Wu Y, Zhao M, Liu C, Zhou L, Shen S, et al. Role of HIF-1alpha in the regulation ACE and ACE2 expression in hypoxic human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2009;297:L631–40.

    Article  CAS  PubMed  Google Scholar 

  42. Xiao F, Li X, Wang J, Cao J. Mechanisms of vascular endothelial cell injury in response to intermittent and/or continuous hypoxia exposure and protective effects of anti-inflammatory and anti-oxidant agents. Sleep Breath. 2019;23:515–22.

    Article  PubMed  Google Scholar 

  43. Flamant L, Toffoli S, Raes M, Michiels C. Hypoxia regulates inflammatory gene expression in endothelial cells. Exp Cell Res. 2009;315:733–47.

    Article  CAS  PubMed  Google Scholar 

  44. Suliman HB, Sweeney TE, Withers CM, Piantadosi CA. Co-regulation of nuclear respiratory factor-1 by NFkappaB and CREB links LPS-induced inflammation to mitochondrial biogenesis. J Cell Sci. 2010;123:2565–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dalmasso C, Patil CN, Yanes Cardozo LL, Romero DG, Maranon RO. Cardiovascular and metabolic consequences of testosterone supplements in young and old male spontaneously hypertensive rats: implications for testosterone supplements in men. J Am Heart Assoc. 2017;6:10.

    Article  Google Scholar 

  46. Velho I, Fighera TM, Ziegelmann PK, Spritzer PM. Effects of testosterone therapy on BMI blood pressure, laboratory profile of transgender men: a systematic review. Andrology. 2017;5:881–8.

    Article  CAS  PubMed  Google Scholar 

  47. Kienitz T, Quinkler M. Testosterone and blood pressure regulation. Kidney Blood Press Res. 2008;31:71–9.

    Article  CAS  PubMed  Google Scholar 

  48. Traish A, Bolanos J, Nair S, Saad F, Morgentaler A. Do androgens modulate the pathophysiological pathways of inflammation? Appraising the contemporary evidence. J Clin Med. 2018;7:12.

    Article  Google Scholar 

  49. Lee OD, Tillman K. An overview of testosterone therapy. Am J Mens Health. 2016;10:68–72.

    Article  PubMed  Google Scholar 

  50. Lo EM, Rodriguez KM, Pastuszak AW, Khera M. Alternatives to testosterone therapy: a review. Sex Med Rev. 2018;6:106–13.

    Article  PubMed  Google Scholar 

  51. Ohlander SJ, Varghese B, Pastuszak AW. Erythrocytosis following testosterone therapy. Sex Med Rev. 2018;6:77–85.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Professor Xia Li at Nantong University, who kindly provided the HUVEC line as a gift. In addition, the authors thank Dr. Zhangji Dong at Nantong University for polishing the manuscript.

Funding

The study was supported by the National Natural Science Foundation of China (31671206, 81702874).

Author information

Authors and Affiliations

  1. Institute of Special Environmental Medicine, Nantong University, Nantong, 226019, Jiangsu, China

    Shan Jiang, Guijuan Chen, Zhihui Yang, Dan Wang, Yapeng Lu, Li Zhu & Xueting Wang

  2. Co-Innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, 226019, Jiangsu, China

    Li Zhu

  3. School of Life Science and Technology, China Pharmaceutical University, Nanjing, China

    Shan Jiang

Authors
  1. Shan Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guijuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhihui Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yapeng Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xueting Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Li Zhu or Xueting Wang.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, S., Chen, G., Yang, Z. et al. Testosterone attenuates hypoxia-induced hypertension by affecting NRF1-mediated transcriptional regulation of ET-1 and ACE. Hypertens Res 44, 1395–1405 (2021). https://doi.org/10.1038/s41440-021-00703-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-021-00703-4

Keywords

This article is cited by

Search

Advanced search

Quick links