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:

Endothelial progenitor cells predict vascular damage progression in naive hypertensive patients according to sex

Abstract

Low levels of endothelial progenitor cells (EPCs) are associated with cardiovascular (CV) morbidity and mortality. Early indicators of vascular damage represent independent predictors of CV prognosis. The aim of this study was to evaluate the possible association of EPCs and circulating cytokine levels with vascular damage markers in naive hypertensive patients according to sex and to evaluate the role of EPCs in vascular damage progression. We enrolled 60 subjects; circulating EPCs were determined by cytometric analysis, and serum cytokines were determined by chemiluminescence microarray technology. Endothelial function was estimated with the measurement of the reactive hyperemia index (RHI), arterial stiffness (AS) was evaluated with the measurement of carotid-femoral pulse wave velocity (PWV) and carotid intima-media thickness (IMT) was determined by a high-resolution ultrasound B-mode system. Patients were evaluated at baseline and after an average follow-up of 3.0 ± 0.6 years. RHI was correlated with EPCs and inversely related to HOMA, TNF-α, IL-6, hs-CRP, and IL-1β. PWV was positively correlated with HOMA, TNF-α, IL-6, IL-1β, and hs-CRP, and it was inversely related to EPCs. An inverse relationship was observed between c-IMT and EPCs and e-GFR. EPCs were the major predictor of the RHI and PWV. After adjustment for vascular index basal values and the other covariates, EPCs explained 17.0%, 27.7%, and 10.6% of the variability in ΔRHI, ΔPWV, and Δc-IMT at follow-up, respectively. Our study results support the hypothesis of an etiological link between circulating EPCs and morphofunctional vascular parameters in hypertensive subjects. Of interest, circulating EPCs, after adjusting for possible confounding factors, may indicate vascular damage progression.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

Peter Libby, Julie E. Buring, … Eldrin F. Lewis

References

  1. Hristov M, Zernecke A, Liehn EA, Weber C. Regulation of endothelial progenitor cell homing after arterial injury. Thromb Haemost. 2007;98:274–7.

    Article  CAS  PubMed  Google Scholar 

  2. Schmidt-Lucke C, Rössig L, Fichtlscherer S, Vasa M, Britten M, Kämper U, et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation. 2005;111:2981–7.

    Article  PubMed  Google Scholar 

  3. Luo S, Xia W, Chen C, Robinson EA, Tao J. Endothelial progenitor cells and hypertension: current concepts and future implications. Clin Sci. 2016;130:2029–42.

    Article  CAS  Google Scholar 

  4. Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005;353:999–1007.

    Article  CAS  PubMed  Google Scholar 

  5. Sciacqua A, Scozzafava A, Pujia A, Maio R, Borrello F, Andreozzi F, et al. Interaction between vascular dysfunction and cardiac mass increases the risk of cardiovascular outcomes in essential hypertension. Eur Heart J. 2005;26:921–7.

    Article  PubMed  Google Scholar 

  6. Liao Y, Chen L, Zeng T, Li Y, Yu F, Hu L, et al. Number of circulating endothelial progenitor cells as a marker of vascular endothelial function for type 2 diabetes. Vasc Med. 2010;15:279–85.

    Article  PubMed  Google Scholar 

  7. Hill JM, Zalos G, Halcox JPJ, Schenke WH, Waclawiw MA, Quyyumi AA, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348:593–600.

    Article  PubMed  Google Scholar 

  8. Avolio AP, Van Bortel LM, Boutouyrie P, Cockcroft JR, McEniery CM, Protogerou AD, et al. Role of pulse pressure amplification in arterial hypertension: experts’ opinion and review of the data. Hypertension. 2009;54:375–83.

    Article  CAS  PubMed  Google Scholar 

  9. Sciacqua A, Maio R, Miceli S, Pascale A, Carullo G, Grillo N, et al. Association between one-hour post-load plasma glucose levels and vascular stiffness in essential hypertension. PLoS ONE. 2012;7:e44470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ceravolo R, Maio R, Pujia A, Sciacqua A, Ventura G, Costa MC, et al. Pulse pressure and endothelial dysfunction in never-treated hypertensive patients. J Am Coll Cardiol. 2003;41:1753–8.

    Article  CAS  PubMed  Google Scholar 

  11. Mattace-Raso F, van der Cammen TJM, Hofman A, van Popele NM, Bos ML, Schalekamp MADH, et al. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation. 2006;113:657–63.

    Article  PubMed  Google Scholar 

  12. Yang Z, Chen L, Su C, Xia W, Wang Y, Wang J, et al. Impaired endothelial progenitor cell activity is associated with reduced arterial elasticity in patients with essential hypertension. Clin Exp Hypertens. 2010;32:444–52.

    Article  PubMed  Google Scholar 

  13. Mandraffino G, Sardo MA, Riggio S, Loddo S, Imbalzano E, Alibrandi A, et al. Circulating progenitor cells are increased in newly diagnosed untreated hypertensive patients with arterial stiffening but normal carotid intima-media thickness. Hypertens Res. 2011;34:876–83.

    Article  CAS  PubMed  Google Scholar 

  14. Marketou ME, Kalyva A, Parthenakis FI, Pontikoglou C, Maragkoudakis S, Kontaraki JE, et al. Circulating endothelial progenitor cells in hypertensive patients with increased arterial stiffness. J Clin Hypertens. 2014;16:295–300.

    Article  CAS  Google Scholar 

  15. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340:115–26.

    Article  CAS  PubMed  Google Scholar 

  16. Perticone F, Maio R, Sciacqua A, Andreozzi F, Iemma G, Perticone M, et al. Endothelial dysfunction and C-reactive protein are risk factors for diabetes in essential hypertension. Diabetes. 2008;57:167–71.

    Article  CAS  PubMed  Google Scholar 

  17. Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care. 2000;23:57–63.

    Article  CAS  PubMed  Google Scholar 

  18. Accattato F, Greco M, Pullano SA, Carè I, Fiorillo AS, Pujia A, et al. Effects of acute physical exercise on oxidative stress and inflammatory status in young, sedentary obese subjects. PLoS ONE. 2017;12:e0178900.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Peters SA, den Ruijter HM, Palmer MK, Grobbee DE, Crouse JR 3rd, O’Leary DH, et al. METEOR Study Investigators. Extensive or restricted ultrasound protocols to measure carotid intima-media thickness: analysis of completeness rates and impact on observed rates of change over time. J Am Soc Echocardiogr. 2012;25:91–100.

    Article  PubMed  Google Scholar 

  20. Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, et al. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010;31:1142–8.

    Article  PubMed  Google Scholar 

  21. Mandraffino G, Imbalzano E, Sardo MA, D’Ascola A, Mamone F, Lo Gullo A, et al. Circulating progenitor cells in hypertensive patients with different degrees of cardiovascular involvement. J Hum Hypertens. 2014;28:543–50.

    Article  CAS  PubMed  Google Scholar 

  22. Aragona CO, Imbalzano E, Mamone F, Cairo V, Lo Gullo A, D’Ascola A, et al. Endothelial progenitor cells for diagnosis and prognosis in cardiovascular disease. Stem Cells Int. 2016;2016:8043792.

    Article  PubMed  CAS  Google Scholar 

  23. Fadini GP, de Kreutzenberg SV, Coracina A, Baesso I, Agostini C, Tiengo A, et al. Circulating CD34+ cells, metabolic syndrome, and cardiovascular risk. Eur Heart J. 2006;27:2247–55.

    Article  CAS  PubMed  Google Scholar 

  24. Andreozzi F, Laratta E, Sciacqua A, Perticone F, Sesti G. Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells. Circ Res. 2004;94:1211–8.

    Article  CAS  PubMed  Google Scholar 

  25. Aicher A, Heeschen C, Dimmeler S. The role of NOS3 in stem cell mobilization. Trends Mol Med. 2004;10:421–5.

    Article  CAS  PubMed  Google Scholar 

  26. Cubbon RM, Kahn MB, Wheatcroft SB. Effects of insulin resistance on endothelial progenitor cells and vascular repair. Clin Sci. 2009;117:173–90.

    Article  CAS  Google Scholar 

  27. Mahmud A, Feely J. Arterial stiffness is related to systemic inflammation in essential hypertension. Hypertension. 2005;46:1118–22.

    Article  CAS  PubMed  Google Scholar 

  28. Tomiyama H, Yamashina A. Non-invasive vascular function tests: their pathophysiological background and clinical application. Circ J. 2010;74:24–33.

    Article  PubMed  Google Scholar 

  29. Mahmud A, Feely J. Arterial stiffness and the renin-angiotensin-aldosterone system. J Renin Angiotensin Aldosterone Syst. 2004;5:102–8.

    Article  CAS  PubMed  Google Scholar 

  30. Lee PS, Poh KK. Endothelial progenitor cells in cardiovascular diseases. World J Stem Cells. 2014;6:355–66.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Raptis AE, Markakis KP, Mazioti MC, Ikonomidis I, Maratou EP, Vlahakos DV, et al. Effect of aliskiren on circulating endothelial progenitor cells and vascular function in patients with type 2 diabetes and essential hypertension. Am J Hypertens. 2015;28:22–9.

    Article  CAS  PubMed  Google Scholar 

  32. Cacciatore F, Bruzzese G, Vitale DF, Liguori A, de Nigris F, Fiorito C, et al. Effects of ACE inhibition on circulating endothelial progenitor cells, vascular damage, and oxidative stress in hypertensive patients. Eur J Clin Pharm. 2011;67:877–83.

    Article  CAS  Google Scholar 

  33. Suzuki R, Fukuda N, Katakawa M, Tsunemi A, Tahira Y, Matsumoto T, et al. Effects of an angiotensin II receptor blocker on the impaired function of endothelial progenitor cells in patients with essential hypertension. Am J Hypertens. 2014;27:695–701.

    Article  CAS  PubMed  Google Scholar 

  34. Chen L, Ding ML, Wu F, He W, Li J, Zhang XY, et al. Impaired endothelial repair capacity of early endothelial progenitor cells in hypertensive patients with primary hyperaldosteronemia: role of 5,6,7,8-tetrahydrobiopterin oxidation and endothelial nitric oxide synthase uncoupling. Hypertension. 2016;67:430–9.

    Article  CAS  PubMed  Google Scholar 

  35. Sugiura T, Kondo T, Kureishi-Bando Y, Numaguchi Y, Yoshida O, Dohi Y, et al. Nifedipine improves endothelial function: role of endothelial progenitor cells. Hypertension. 2008;52:491–8.

    Article  CAS  PubMed  Google Scholar 

  36. Yao EH, Fukuda N, Matsumoto T, Katakawa M, Yamamoto C, Han Y, et al. Effects of the antioxidative beta-blocker celiprolol on endothelial progenitor cells in hypertensive rats. Am J Hypertens. 2008;21:1062–8.

    Article  CAS  PubMed  Google Scholar 

  37. Pastori D, Farcomeni A, Milanese A, Del Sole F, Menichelli D, Hiatt WR, et al. Statins and major adverse limb events in patients with peripheral artery disease: a systematic review and meta-analysis. Thromb Haemost. 2020;120:866–75.

    Article  PubMed  Google Scholar 

  38. Golab-Janowska M, Paczkowska E, Machalinski B, Meller A, Kotlega D, Safranow K, et al. Statins therapy is associated with increased populations of early endothelial progenitor (CD133+/VEGFR2+) and endothelial (CD34-/CD133-/VEGFR2+) cells in patients with acute ischemic stroke. Curr Neurovasc Res. 2018;15:120–8.

    Article  CAS  PubMed  Google Scholar 

  39. Park A, Barrera-Ramirez J, Ranasinghe I, Pilon S, Sy R, Fergusson D, et al. Use of statins to augment progenitor cell function in preclinical and clinical studies of regenerative therapy: a systematic review. Stem Cell Rev Rep. 2016;12:327–39.

    Article  CAS  PubMed  Google Scholar 

  40. Briguori C, Quintavalle C, D’Alessio F, Donahue M, Roscigno G, De Micco F, et al. Impact of statin therapy intensity on endothelial progenitor cells after percutaneous coronary intervention in diabetic patients. The REMEDY-EPC late study. Int J Cardiol. 2017;244:112–8.

    Article  PubMed  Google Scholar 

  41. Chantzichristos VG, Agouridis AP, Moutzouri E, Stellos K, Elisaf MS, et al. Effect of rosuvastatin or its combination with omega-3 fatty acids on circulating CD34(+) progenitor cells and on endothelial colony formation in patients with mixed dyslipidaemia. Atherosclerosis. 2016;251:240–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed to data collection and analysis, drafting of the article, and interpretation of the results. All authors provided critical feedback, assisted in the revision of the article, and approved the final version.

Corresponding author

Correspondence to Angela Sciacqua.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the local ethics committee (Comitato Etico Azienda Ospedaliera “Mater Domini”) (cod. protocol number 2021.63).

Informed consent

Informed consent was obtained from all subjects involved in the study.

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

Cassano, V., Tripepi, G., Perticone, M. et al. Endothelial progenitor cells predict vascular damage progression in naive hypertensive patients according to sex. Hypertens Res 44, 1451–1461 (2021). https://doi.org/10.1038/s41440-021-00716-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-021-00716-z

Keywords

This article is cited by

Search

Quick links