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Endothelial function and endothelial progenitor cells in systemic lupus erythematosus

Nature Reviews Rheumatology volume 18, pages 286–300 (2022)Cite this article

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Abstract

The observations that traditional cardiovascular disease (CVD) risk factors fail to fully account for the excessive cardiovascular mortality in patients with systemic lupus erythematosus (SLE) compared with the general population have prompted in-depth investigations of non-traditional, SLE-related risk factors that contribute to cardiovascular complications in patients with SLE. Of the various perturbations of vascular physiology, endothelial dysfunction, which is believed to occur in the earliest step of atherosclerosis, has been extensively investigated for its contribution to CVD risk in SLE. Endothelial progenitor cells (EPCs), which play a crucial part in vascular repair, neovascularization and maintenance of endothelial function, are quantitatively and functionally reduced in patients with SLE. Yet, the lack of a unified definition of EPCs, standardization of the quantity and functional assessment of EPCs as well as endothelial function measurement pose challenges to the translation of endothelial function measurements and EPC levels into prognostic markers for CVD in patients with SLE. This Review discusses factors that contribute to CVD in SLE, with particular focus on how endothelial function and EPCs are evaluated currently, and how EPCs are quantitatively and functionally altered in patients with SLE. Potential strategies for the use of endothelial function measurements and EPC quantification as prognostic markers of CVD in patients with SLE, and the limitations of their prognostication potential, are also discussed.

Key points

  • Traditional cardiovascular disease (CVD) risk factors are prevalent in patients with systemic lupus erythematosus (SLE), but this observation cannot fully explain the excess of cardiovascular mortality and morbidity in these patients.

  • Endothelium-dependent flow-mediated dilation of the brachial artery, a common biophysical measure of endothelial function, is impaired in patients with SLE, even if they do not present with CVD.

  • Impaired endothelial function is associated with increased diastolic blood pressure, inflammation and vertebral bone loss in patients with SLE.

  • Endothelial progenitor cells (EPCs) are reduced quantitatively and functionally in patients with SLE, compared with healthy individuals.

  • Antimalarial drug use might be associated with elevation of levels of circulating angiogenic cells in patients with SLE.

  • Standardization of the definition and functional characterization of EPCs is paramount before EPCs can be used as prognostic biomarkers for CVD in patients with SLE.

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Fig. 1: Relationships between endothelial function, EPCs and CVD in SLE.
Fig. 2: Type 1 interferon and other key mediators detrimental to endothelial cells and EPCs.
Fig. 3: Factors that influence endothelial function in SLE.
Fig. 4: Regulation of EPCs by different therapeutic approaches and their prognostic potential for CVD in SLE.

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References

  1. Barbhaiya, M. et al. Comparative risks of cardiovascular disease in patients with systemic lupus erythematosus, diabetes mellitus, and in general Medicaid recipients. Arthritis Care Res. 72, 1431–1439 (2020).

    Article  Google Scholar 

  2. Jonsson, H., Nived, O. & Sturfelt, G. Outcome in systemic lupus erythematosus: a prospective study of patients from a defined population. Medicine 68, 141–150 (1989).

    Article  CAS  PubMed  Google Scholar 

  3. Manzi, S. et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am. J. Epidemiol. 145, 408–415 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Bernatsky, S. et al. Mortality in systemic lupus erythematosus. Arthritis Rheum. 54, 2550–2557 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Yurkovich, M., Vostretsova, K., Chen, W. & Aviña-Zubieta, J. A. Overall and cause-specific mortality in patients with systemic lupus erythematosus: a meta-analysis of observational studies. Arthritis Care Res. 66, 608–616 (2014).

    Article  Google Scholar 

  6. Goldberg, R. J., Urowitz, M. B., Ibañez, D., Nikpour, M. & Gladman, D. D. Risk factors for development of coronary artery disease in women with systemic lupus erythematosus. J. Rheumatol. 36, 2454–2461 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Colombo, B. M. et al. Traditional and non traditional risk factors in accelerated atherosclerosis in systemic lupus erythematosus: role of vascular endothelial growth factor (VEGATS Study). Autoimmun. Rev. 8, 309–315 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Moghaddam, B., Marozoff, S., Li, L., Sayre, E. C. & Zubieta, J. A. A. All-cause and cause-specific mortality in systemic lupus erythematosus: a population-based study. Rheumatology https://doi.org/10.1093/rheumatology/keab362 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Leonard, D. et al. Coronary heart disease in systemic lupus erythematosus is associated with interferon regulatory factor-8 gene variants. Circ. Cardiovasc. Genet. 6, 255–263 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Bahrehmand, F. et al. Matrix metalloproteinase-2 functional promoter polymorphism G1575A is associated with elevated circulatory MMP-2 levels and increased risk of cardiovascular disease in systemic lupus erythematosus patients. Lupus 21, 616–624 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Bicakcigil, M., Tasan, D., Tasdelen, N., Mutlu, N. & Yavuz, S. Role of fibrinolytic parameters and plasminogen activator inhibitor 1 (PAI-1) promoter polymorphism on premature atherosclerosis in SLE patients. Lupus 20, 1063–1071 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Troelsen, L. N., Garred, P., Christiansen, B., Torp-Pedersen, C. & Jacobsen, S. Genetically determined serum levels of mannose-binding lectin correlate negatively with common carotid intima-media thickness in systemic lupus erythematosus. J. Rheumatol. 37, 1815–1821 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Marasini, B. et al. Genetic contribution to carotid vascular disease in patients with systemic lupus erythematosus. J. Clin. Immunol. 28, 131–133 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Szalai, A. J. et al. Systemic lupus erythematosus in a multiethnic US Cohort (LUMINA). XXX: association between C-reactive protein (CRP) gene polymorphisms and vascular events. Rheumatology 44, 864–868 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Frieri, M. Accelerated atherosclerosis in systemic lupus erythematosus: role of proinflammatory cytokines and therapeutic approaches. Curr. Allergy Asthma Rep. 12, 25–32 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Medeiros, P. B. S. et al. Disease activity index is associated with subclinical atherosclerosis in childhood-onset systemic lupus erythematosus. Pediatr. Rheumatol. Online J. 19, 35 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Faurschou, M. et al. High risk of ischemic heart disease in patients with lupus nephritis. J. Rheumatol. 38, 2400–2405 (2011).

    Article  PubMed  Google Scholar 

  18. Ajeganova, S., Hafström, I. & Frostegård, J. Patients with SLE have higher risk of cardiovascular events and mortality in comparison with controls with the same levels of traditional risk factors and intima-media measures, which is related to accumulated disease damage and antiphospholipid syndrome: a case-control study over 10 years. Lupus Sci. Med. 8, e000454 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Montarello, N. J., Nguyen, M. T., Wong, D. T. L., Nicholls, S. J. & Psaltis, P. J. Inflammation in coronary atherosclerosis and its therapeutic implications. Cardiovasc Drugs Ther. https://doi.org/10.1007/s10557-020-07106-6 (2020).

    Article  PubMed  Google Scholar 

  20. Oikonomou, E. et al. A link between inflammation and thrombosis in atherosclerotic cardiovascular diseases: clinical and therapeutic implications. Atherosclerosis 309, 16–26 (2020).

    Article  CAS  PubMed  Google Scholar 

  21. Miller, A. M. & McInnes, I. B. Cytokines as therapeutic targets to reduce cardiovascular risk in chronic inflammation. Curr. Pharm. Des. 17, 1–8 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Steyers, C. M. 3rd & Miller, F. J. Jr Endothelial dysfunction in chronic inflammatory diseases. Int. J. Mol. Sci. 15, 11324–11349 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Sitia, S. et al. From endothelial dysfunction to atherosclerosis. Autoimmun. Rev. 9, 830–834 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Reynolds, J. A. et al. Brief report: vitamin D deficiency is associated with endothelial dysfunction and increases type I interferon gene expression in a murine model of systemic lupus erythematosus. Arthritis Rheumatol. 68, 2929–2935 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. Stalc, M., Tomsic, M., Jezovnik, M. K. & Poredos, P. Endothelium-dependent and independent dilation capability of peripheral arteries in patients with systemic lupus erythematosus and antiphospholipid syndrome. Clin. Exp. Rheumatol. 29, 616–623 (2011).

    CAS  PubMed  Google Scholar 

  26. Johnson, S. R. et al. Impaired brachial artery endothelium dependent flow mediated dilation in systemic lupus erythematosus: preliminary observations. Lupus 13, 590–593 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Kiss, E. et al. Reduced flow-mediated vasodilation as a marker for cardiovascular complications in lupus patients. J. Autoimmun. 27, 211–217 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Ghosh, P. et al. Subclinical atherosclerosis and endothelial dysfunction in young South-Asian patients with systemic lupus erythematosus. Clin. Rheumatol. 28, 1259–1265 (2009).

    Article  PubMed  Google Scholar 

  29. Go, E. & Yoder, M. C. Identification of endothelial cells and their progenitors. Methods Mol. Biol. 2206, 27–37 (2021).

    Article  PubMed  CAS  Google Scholar 

  30. Mao, S. Z., Ye, X., Liu, G., Song, D. & Liu, S. F. Resident endothelial cells and endothelial progenitor cells restore endothelial barrier function after inflammatory lung injury. Arterioscler. Thromb. Vasc. Biol. 35, 1635–1644 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Baker, J. F. et al. Circulating endothelial progenitor cells are reduced in SLE in the absence of coronary artery calcification. Rheumatol. Int. 32, 997–1002 (2012).

    Article  PubMed  Google Scholar 

  32. Westerweel, P. E. et al. Haematopoietic and endothelial progenitor cells are deficient in quiescent systemic lupus erythematosus. Ann. Rheum. Dis. 66, 865–870 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Denny, M. F. et al. Interferon-alpha promotes abnormal vasculogenesis in lupus: a potential pathway for premature atherosclerosis. Blood 110, 2907–2915 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lee, P. Y. et al. Type I interferon as a novel risk factor for endothelial progenitor cell depletion and endothelial dysfunction in systemic lupus erythematosus. Arthritis Rheum. 56, 3759–3769 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Moonen, J. R. et al. Reduced number and impaired function of circulating progenitor cells in patients with systemic lupus erythematosus. Arthritis Res. Ther. 9, R84 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Huang, J., Kow, N. Y., Lee, H. Y., Fairhurst, A. M. & Mak, A. CD34+CD133+CD309+ circulating angiogenic cell level is reduced but positively related to hydroxychloroquine use in SLE patients — a case-control study and meta-regression analysis. Rheumatology 60, 3936–3944 (2021).

    Article  PubMed  Google Scholar 

  37. Kim, J. Y. et al. Osteoprotegerin causes apoptosis of endothelial progenitor cells by induction of oxidative stress. Arthritis Rheum. 65, 2172–2182 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. Mak, A. & Kow, N. Y. Imbalance between endothelial damage and repair: a gateway to cardiovascular disease in systemic lupus erythematosus. Biomed. Res. Int. 2014, 178721 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Ding, X., Xiang, W. & He, X. IFN-I mediates dysfunction of endothelial progenitor cells in atherosclerosis of systemic lupus erythematosus. Front. Immunol. 11, 581385 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Komici, K. et al. Systemic lupus erythematosus, endothelial progenitor cells and intracellular Ca2+ signaling: a novel approach for an old disease. J. Autoimmun. 112, 102486 (2020).

    Article  CAS  PubMed  Google Scholar 

  41. Sánchez-Pérez, H. et al. Impaired HDL cholesterol efflux capacity in systemic lupus erythematosus patients is related to subclinical carotid atherosclerosis. Rheumatology 59, 2847–2856 (2020).

    Article  PubMed  CAS  Google Scholar 

  42. Quevedo-Abeledo, J. C. et al. Differences in HDL-cholesterol efflux capacity between patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Care Res. https://doi.org/10.1002/acr.24407 (2020).

    Article  Google Scholar 

  43. Li, J. et al. Novel insights: dynamic foam cells derived from the macrophage in atherosclerosis. J. Cell Physiol. 236, 6154–6167 (2021).

    Article  CAS  PubMed  Google Scholar 

  44. Smith, C. K. et al. Lupus high-density lipoprotein induces proinflammatory responses in macrophages by binding lectin-like oxidised low-density lipoprotein receptor 1 and failing to promote activating transcription factor 3 activity. Ann. Rheum. Dis. 76, 602–611 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. McMahon, M. et al. A panel of biomarkers is associated with increased risk of the presence and progression of atherosclerosis in women with systemic lupus erythematosus. Arthritis Rheumatol. 66, 130–139 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Parikh, S. V., Almaani, S., Brodsky, S. & Rovin, B. H. Update on lupus nephritis: core curriculum 2020. Am. J. Kidney Dis. 76, 265–281 (2020).

    Article  PubMed  Google Scholar 

  47. Mak, A., Cheung, M. W., Chiew, H. J., Liu, Y. & Ho, R. C. Global trend of survival and damage of systemic lupus erythematosus: meta-analysis and meta-regression of observational studies from the 1950s to 2000s. Semin. Arthritis Rheum. 41, 830–839 (2012).

    Article  PubMed  Google Scholar 

  48. Hermansen, M. L., Lindhardsen, J., Torp-Pedersen, C., Faurschou, M. & Jacobsen, S. The risk of cardiovascular morbidity and cardiovascular mortality in systemic lupus erythematosus and lupus nephritis: a Danish nationwide population-based cohort study. Rheumatology 56, 709–715 (2017).

    PubMed  Google Scholar 

  49. Liu, Y. & Kaplan, M. J. Cardiovascular disease in systemic lupus erythematosus: an update. Curr. Opin. Rheumatol. 30, 441–448 (2018).

    Article  PubMed  Google Scholar 

  50. Sethna, C. B., Merchant, K. & Reyes, A. Cardiovascular disease risk in children with kidney disease. Semin. Nephrol. 38, 298–313 (2018).

    Article  PubMed  Google Scholar 

  51. Kahn, M. R., Robbins, M. J., Kim, M. C. & Fuster, V. Management of cardiovascular disease in patients with kidney disease. Nat. Rev. Cardiol. 10, 261–273 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Sun, E. Y., Alvarez, C. & Sheikh, S. Z. Association of lupus nephritis with coronary artery disease by ISN/RPS classification: results from a large real-world lupus population. ACR Open Rheumatol. 1, 244–250 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Frangou, E., Georgakis, S. & Bertsias, G. Update on the cellular and molecular aspects of lupus nephritis. Clin. Immunol. 216, 108445 (2020).

    Article  CAS  PubMed  Google Scholar 

  54. Dimou, P. et al. The human glomerular endothelial cells are potent pro-inflammatory contributors in an in vitro model of lupus nephritis. Sci. Rep. 9, 8348 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Deng, W. et al. CD8+CD103+ iTregs inhibit the progression of lupus nephritis by attenuating glomerular endothelial cell injury. Rheumatology 58, 2039–2050 (2019).

    Article  CAS  PubMed  Google Scholar 

  56. Choe, J. Y., Lee, S. S., Kwak, S. G. & Kim, S. K. Anti-Sm antibody, damage index, and corticosteroid use are associated with cardiac involvement in systemic lupus erythematosus: data from a prospective registry study. J. Korean Med. Sci. 35, e139 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Urowitz, M. B. et al. Accrual of atherosclerotic vascular events in a multicenter inception systemic lupus erythematosus cohort. Arthritis Rheumatol. 72, 1734–1740 (2020).

    Article  CAS  PubMed  Google Scholar 

  58. Fasano, S. et al. Prolonged remission is associated with a reduced risk of cardiovascular disease in patients with systemic lupus erythematosus: a GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) study. Clin. Rheumatol. 38, 457–463 (2019).

    Article  PubMed  Google Scholar 

  59. Asanuma, Y. et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N. Engl. J. Med. 349, 2407–2415 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Rho, Y. H. et al. Novel cardiovascular risk factors in premature coronary atherosclerosis associated with systemic lupus erythematosus. J. Rheumatol. 35, 1789–1794 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Yiu, K. H. et al. Pattern of arterial calcification in patients with systemic lupus erythematosus. J. Rheumatol. 36, 2212–2217 (2019).

    Article  CAS  Google Scholar 

  62. Kiani, A. N. et al. Coronary calcification in SLE: comparison with the multi-ethnic study of atherosclerosis. Rheumatology 54, 1976–1981 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Khan, A., Arbab-Zadeh, A., Kiani, A. N., Magder, L. S. & Petri, M. Progression of noncalcified and calcified coronary plaque by CT angiography in SLE. Rheumatol. Int. 37, 59–65 (2017).

    Article  CAS  PubMed  Google Scholar 

  64. Kiani, A. N., Magder, L. S. & Petri, M. Mycophenolate mofetil (MMF) does not slow the progression of subclinical atherosclerosis in SLE over 2 years. Rheumatol. Int. 32, 2701–2705 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Evans, C. E., Iruela-Arispe, M. L. & Zhao, Y. Y. Mechanisms of endothelial regeneration and vascular repair and their application to regenerative medicine. Am. J. Pathol. 191, 52–65 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Konukoglu, D. & Uzun, H. Endothelial dysfunction and hypertension. Adv. Exp. Med. Biol. 956, 511–540 (2017).

    Article  PubMed  Google Scholar 

  67. Bai, B. et al. NLRP3 inflammasome in endothelial dysfunction. Cell Death Dis. 11, 776 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tabrizi, R. et al. The effects of vitamin D supplementation on markers related to endothelial function among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of clinical trials. Horm. Metab. Res. 50, 587–596 (2018).

    Article  CAS  PubMed  Google Scholar 

  69. Simsek, E. C. et al. Endothelial dysfunction in patients with myocardial ischemia or infarction and nonobstructive coronary arteries. J. Clin. Ultrasound 49, 334–340 (2021).

    Article  PubMed  Google Scholar 

  70. Koo, B. K., Chung, W. Y. & Moon, M. K. Peripheral arterial endothelial dysfunction predicts future cardiovascular events in diabetic patients with albuminuria: a prospective cohort study. Cardiovasc. Diabetol. 19, 82 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Migliacci, R. et al. Walking-induced endothelial dysfunction predicts ischemic cardiovascular events in patients with intermittent claudication. Vasc. Med. 26, 394–400 (2021).

    Article  PubMed  Google Scholar 

  72. Schächinger, V., Britten, M. B. & Zeiher, A. M. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101, 1899–1906 (2000).

    Article  PubMed  Google Scholar 

  73. Halcox, J. P. et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation 106, 653–658 (2002).

    Article  PubMed  Google Scholar 

  74. Barsalou, J. et al. Impact of disease duration on vascular surrogates of early atherosclerosis in childhood-onset systemic lupus erythematosus. Arthritis Rheumatol. 68, 237–246 (2016).

    Article  CAS  PubMed  Google Scholar 

  75. Taraborelli, M. et al. Endothelial dysfunction in early systemic lupus erythematosus patients and controls without previous cardiovascular events. Arthritis Care Res. 70, 1277–1283 (2018).

    Article  CAS  Google Scholar 

  76. Wennmalm, A. Endothelial nitric oxide and cardiovascular disease. J. Intern. Med. 235, 317–327 (1994).

    Article  CAS  PubMed  Google Scholar 

  77. Furchgott, R. F. & Zawadzki, J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288, 373–376 (1980).

    Article  CAS  PubMed  Google Scholar 

  78. Soga, J. et al. Relationship between augmentation index and flow-mediated vasodilation in the brachial artery. Hypertens. Res. 31, 1293–1298 (2008).

    Article  PubMed  Google Scholar 

  79. Gokce, N. et al. Effects of race and hypertension on flow-mediated and nitroglycerin-mediated dilation of the brachial artery. Hypertension 38, 1349–1354 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Mak, A., Liu, Y. & Ho, R. C. Endothelium-dependent but not endothelium-independent flow-mediated dilation is significantly reduced in patients with systemic lupus erythematosus without vascular events: a metaanalysis and metaregression. J. Rheumatol. 38, 1296–1303 (2011).

    Article  PubMed  Google Scholar 

  81. Mak, A. et al. Endothelial dysfunction in systemic lupus erythematosus — a case-control study and an updated meta-analysis and meta-regression. Sci. Rep. 7, 7320 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Riancho-Zarrabeitia, L. et al. Antiphospholipid syndrome (APS) in patients with systemic lupus erythematosus (SLE) implies a more severe disease with more damage accrual and higher mortality. Lupus 29, 1556–1565 (2020).

    Article  CAS  PubMed  Google Scholar 

  83. Ramsey-Goldman, R. & Manzi, S. Association of osteoporosis and cardiovascular disease in women with systemic lupus erythematosus. Arthritis Rheum. 44, 2338–2341 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Mak, A. et al. Lumbar spine bone mineral density predicts endothelial reactivity in patients with systemic lupus erythematosus. Clin. Exp. Rheumatol. 29, 261–268 (2011).

    CAS  PubMed  Google Scholar 

  85. Zhu, J. et al. The association of endothelial nitric oxide synthase gene single nucleotide polymorphisms with paediatric systemic lupus erythematosus. Clin. Exp. Rheumatol. 36, 508–512 (2018).

    PubMed  Google Scholar 

  86. Katkam, S. K., Indumathi, B., Tasneem, F. S. D., Rajasekhar, L. & Kutala, V. K. Impact of eNOS 27-bp VNTR (4b/a) gene polymorphism with the risk of Systemic Lupus Erythematosus in south Indian subjects. Gene 658, 105–112 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Hasni, S. A. et al. Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus. Nat. Commun. 12, 3391 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Santos, M. J. et al. Early vascular alterations in SLE and RA patients — a step towards understanding the associated cardiovascular risk. PLoS One 7, e44668 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Tydén, H. et al. Low plasma concentrations of apolipoprotein M are associated with disease activity and endothelial dysfunction in systemic lupus erythematosus. Arthritis Res. Ther. 21, 110 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Fusco, E. et al. Preclinical vascular alterations in obese adolescents detected by Laser-Doppler Flowmetry technique. Nutr. Metab. Cardiovasc. Dis. 30, 306–312 (2020).

    Article  CAS  PubMed  Google Scholar 

  91. Tydén, H. et al. Endothelial dysfunction is associated with activation of the type I interferon system and platelets in patients with systemic lupus erythematosus. RMD Open 3, e000508 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Indraccolo, S. et al. Identification of genes selectively regulated by IFNs in endothelial cells. J. Immunol. 178, 1122–1135 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Hsu, K. S. et al. Dual regulation of Stat1 and Stat3 by the tumor suppressor protein PML contributes to interferon α-mediated inhibition of angiogenesis. J. Biol. Chem. 292, 10048–10060 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Niessner, A. & Weyand, C. M. Dendritic cells in atherosclerotic disease. Clin. Immunol. 134, 25–32 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Higashiyama, M. et al. Interferon-α increases monocyte migration via platelet-monocyte interaction in murine intestinal microvessels. Clin. Exp. Immunol. 162, 156–162 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Patiño-Trives, A. M. et al. Anti-dsDNA antibodies increase the cardiovascular risk in systemic lupus erythematosus promoting a distinctive immune and vascular activation. Arterioscler. Thromb. Vasc. Biol. 41, 2417–2430 (2021).

    Article  PubMed  Google Scholar 

  97. Campos-López, B. et al. Association of cardiometabolic risk status with clinical activity and damage in systemic lupus erythematosus patients: a cross-sectional study. Clin. Immunol. 222, 108637 (2021).

    Article  PubMed  CAS  Google Scholar 

  98. Rodríguez-Calvo, R. et al. Low-density lipoprotein from active SLE patients is more atherogenic to endothelial cells than low-density lipoprotein from the same patients during remission. Rheumatology 60, 866–871 (2021).

    Article  PubMed  CAS  Google Scholar 

  99. Theofilis, P. et al. Inflammatory mechanisms contributing to endothelial dysfunction. Biomedicines 9, 781 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hernandez, N. M., Casselbrant, A., Joshi, M., Johansson, B. R. & Sumitran-Holgersson, S. Antibodies to kidney endothelial cells contribute to a “leaky” glomerular barrier in patients with chronic kidney diseases. Am. J. Physiol. Renal Physiol. 302, F884–F894 (2012).

    Article  PubMed  Google Scholar 

  101. Velásquez, M., Rojas, M., Abrahams, V. M., Escudero, C. & Cadavid, Á. P. Mechanisms of endothelial dysfunction in antiphospholipid syndrome: association with clinical manifestations. Front. Physiol. 9, 1840 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Mancardi, D. et al. Endothelial dysfunction and cardiovascular risk in lupus nephritis: new roles for old players? Eur. J. Clin. Invest. 51, e13441 (2021).

    Article  CAS  PubMed  Google Scholar 

  103. Valer, P., Paul, B., Eugenia, B. & Camelia, B. Annexin A5 as independent predictive biomarker for subclinical atherosclerosis and endothelial dysfunction in systemic lupus erythematosus patients. Clin. Lab. 59, 359–367 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Mobarrez, F. et al. Microparticles in the blood of patients with systemic lupus erythematosus (SLE): phenotypic characterization and clinical associations. Sci. Rep. 6, 36025 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Martínez, M. C., Tesse, A., Zobairi, F. & Andriantsitohaina, R. Shed membrane microparticles from circulating and vascular cells in regulating vascular function. Am. J. Physiol. Heart Circ. Physiol. 288, H1004–H1009 (2005).

    Article  PubMed  CAS  Google Scholar 

  106. Shao, W. H. The role of microparticles in rheumatic diseases and their potentials as therapeutic tools. J. Mol. Immunol. 1, 101 (2016).

    PubMed  PubMed Central  Google Scholar 

  107. Puddu, P., Puddu, G. M., Cravero, E., Muscari, S. & Muscari, A. The involvement of circulating microparticles in inflammation, coagulation and cardiovascular diseases. Can. J. Cardiol. 26, 140–145 (2010).

    Article  PubMed  Google Scholar 

  108. Markiewicz, M., Richard, E., Marks, N. & Ludwicka-Bradley, A. Impact of endothelial microparticles on coagulation, inflammation, and angiogenesis in age-related vascular diseases. J. Aging Res. 2013, 734509 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Mobarrez, F. et al. Microparticles in the blood of patients with SLE: size, content of mitochondria and role in circulating immune complexes. J. Autoimmun. 102, 142–149 (2019).

    Article  CAS  PubMed  Google Scholar 

  110. Combes, V. et al. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J. Clin. Invest. 104, 93–102 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tsokos, G. C., Lo, M. S., Costa Reis, P. & Sullivan, K. E. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat. Rev. Rheumatol. 12, 716–730 (2016).

    Article  CAS  PubMed  Google Scholar 

  112. Parker, B. et al. Suppression of inflammation reduces endothelial microparticles in active systemic lupus erythematosus. Ann. Rheum. Dis. 73, 1144–1150 (2014).

    Article  CAS  PubMed  Google Scholar 

  113. Atehortúa, L. et al. Endothelial activation and injury by microparticles in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res. Ther. 21, 34 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  114. López, P., Rodríguez-Carrio, J., Martínez-Zapico, A., Caminal-Montero, L. & Suárez, A. Circulating microparticle subpopulations in systemic lupus erythematosus are affected by disease activity. Int. J. Cardiol. 236, 138–144 (2017).

    Article  PubMed  Google Scholar 

  115. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Garcia-Romo, G. S. et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra20 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Gupta, A. K. et al. Activated endothelial cells induce neutrophil extracellular traps and are susceptible to NETosis-mediated cell death. FEBS Lett. 584, 3193–3197 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Carmona-Rivera, C., Zhao, W., Yalavarthi, S. & Kaplan, M. J. Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann. Rheum. Dis. 74, 1417–1424 (2015).

    Article  CAS  PubMed  Google Scholar 

  119. von Brühl, M. L. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J. Exp. Med. 209, 819–835 (2012).

    Article  CAS  Google Scholar 

  120. Massberg, S. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat. Med. 16, 887–896 (2010).

    Article  CAS  PubMed  Google Scholar 

  121. Pieterse, E. et al. Neutrophil extracellular traps drive endothelial-to-mesenchymal transition. Arterioscler. Thromb. Vasc. Biol. 37, 1371–1379 (2017).

    Article  CAS  PubMed  Google Scholar 

  122. Lande, R. et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra19 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Döring, Y. et al. Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation 125, 1673–1683 (2012).

    Article  PubMed  CAS  Google Scholar 

  124. Knight, J. S. et al. Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann. Rheum. Dis. 74, 2199–2206 (2015).

    Article  CAS  PubMed  Google Scholar 

  125. Pardanaud, L., Altmann, C., Kitos, P., Dieterlen-Lievre, F. & Buck, C. A. Vasculogenesis in the early quail blastodisc as studied with a monoclonal antibody recognizing endothelial cells. Development 100, 339–349 (1987).

    Article  CAS  PubMed  Google Scholar 

  126. Asahara, T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964–967 (1997).

    Article  CAS  PubMed  Google Scholar 

  127. Chong, M. S., Ng, W. K. & Chan, J. K. Concise review: endothelial progenitor cells in regenerative medicine: applications and challenges. Stem Cell Transl. Med. 5, 530–538 (2016).

    Article  CAS  Google Scholar 

  128. Purhonen, S. et al. Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc. Natl Acad. Sci. USA 105, 6620–6625 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Barber, C. L. & Iruela-Arispe, M. L. The ever-elusive endothelial progenitor cell: identities, functions and clinical implications. Pediatr. Res. 59, 26R–32R (2006).

    Article  PubMed  Google Scholar 

  130. Basile, D. P. & Yoder, M. C. Circulating and tissue resident endothelial progenitor cells. J. Cell Physiol. 229, 10–16 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Schmeisser, A. & Strasser, R. H. Phenotypic overlap between hematopoietic cells with suggested angioblastic potential and vascular endothelial cells. J. Hematother. Stem Cell Res. 11, 69–79 (2002).

    Article  CAS  PubMed  Google Scholar 

  132. Schmeisser, A., Graffy, C., Daniel, W. G. & Strasser, R. H. Phenotypic overlap between monocytes and vascular endothelial cells. Adv. Exp. Med. Biol. 522, 59–74 (2003).

    Article  CAS  PubMed  Google Scholar 

  133. Desai, A. et al. Microarray-based characterization of a colony assay used to investigate endothelial progenitor cells and relevance to endothelial function in humans. Arterioscler. Thromb. Vasc. Biol. 29, 121–127 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Medina, R. J. et al. Myeloid angiogenic cells act as alternative M2 macrophages and modulate angiogenesis through interleukin-8. Mol. Med. 17, 1045–1055 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zhao, H. & He, Y. The inhibitory effect of lysophosphatidylcholine on proangiogenesis of human CD34+ cells derived endothelial progenitor cells. Front. Mol. Biosci. 8, 682367 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Liu, Y. et al. Contrasting effects of vasculogenic induction upon biaxial bioreactor stimulation of mesenchymal stem cells and endothelial progenitor cells cocultures in three-dimensional scaffolds under in vitro and in vivo paradigms for vascularized bone tissue engineering. Tissue Eng. A 19, 893–904 (2013).

    Article  CAS  Google Scholar 

  137. Ingram, D. A. et al. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 104, 2752–2760 (2004).

    Article  CAS  PubMed  Google Scholar 

  138. Yoder, M. C. et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 109, 1801–1809 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Medina, R. J. et al. Endothelial progenitors: a consensus statement on nomenclature. Stem Cell Transl. Med. 6, 1316–1320 (2017).

    Article  Google Scholar 

  140. Spinelli, F. R. et al. B lymphocyte stimulator modulates number and function of endothelial progenitor cells in systemic lupus erythematosus. Arthritis Res. Ther. 21, 245 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Deng, X. L., Li, X. X., Liu, X. Y., Sun, L. & Liu, R. Comparative study on circulating endothelial progenitor cells in systemic lupus erythematosus patients at active stage. Rheumatol. Int. 30, 1429–1436 (2010).

    Article  PubMed  Google Scholar 

  142. Kahlenberg, J. M. et al. Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus. J. Immunol. 187, 6143–6156 (2011).

    Article  CAS  PubMed  Google Scholar 

  143. Thacker, S. G. et al. The detrimental effects of IFN-α on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction. J. Immunol. 185, 4457–4469 (2010).

    Article  CAS  PubMed  Google Scholar 

  144. Ablin, J. N. et al. Enhanced adhesive properties of endothelial progenitor cells (EPCs) in patients with SLE. Rheumatol. Int. 31, 773–778 (2011).

    Article  PubMed  Google Scholar 

  145. Grisar, J. et al. Systemic lupus erythematosus patients exhibit functional deficiencies of endothelial progenitor cells. Rheumatology 47, 1476–1483 (2008).

    Article  CAS  PubMed  Google Scholar 

  146. Distler, J. H. et al. EULAR Scleroderma Trials and Research group statement and recommendations on endothelial precursor cells. Ann. Rheum. Dis. 68, 163–168 (2009).

    Article  CAS  PubMed  Google Scholar 

  147. Kuwana, M. & Okazaki, Y. Quantification of circulating endothelial progenitor cells in systemic sclerosis: a direct comparison of protocols. Ann. Rheum. Dis. 71, 617–620 (2012).

    Article  PubMed  Google Scholar 

  148. Williamson, K. A. et al. Age-related impairment of endothelial progenitor cell migration correlates with structural alterations of heparan sulfate proteoglycans. Aging Cell 12, 139–147 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. Ebner, P. et al. Accumulation of VEGFR-2+/CD133+ cells and decreased number and impaired functionality of CD34+/VEGFR-2+ cells in patients with SLE. Rheumatology 49, 63–72 (2010).

    Article  CAS  PubMed  Google Scholar 

  150. Ding, X. et al. Neutralizing interferon-α blocks inflammation-mediated vascular injury via PI3K and AMPK in systemic lupus erythematosus. Immunology https://doi.org/10.1111/imm.13379 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Thacker, S. G. et al. Type I interferons modulate vascular function, repair, thrombosis, and plaque progression in murine models of lupus and atherosclerosis. Arthritis Rheum. 64, 2975–2985 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Denny, M. F. et al. A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. J. Immunol. 184, 3284–3297 (2010).

    Article  CAS  PubMed  Google Scholar 

  153. Möckel, T., Basta, F., Weinmann-Menke, J. & Schwarting, A. B cell activating factor (BAFF): structure, functions, autoimmunity and clinical implications in Systemic Lupus Erythematosus (SLE). Autoimmun. Rev. 20, 102736 (2021).

    Article  PubMed  CAS  Google Scholar 

  154. Naserian, S. et al. The TNF/TNFR2 signaling pathway is a key regulatory factor in endothelial progenitor cell immunosuppressive effect. Cell Commun. Signal. 18, 94 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Mak, A., Tang, C. S. & Ho, R. C. Serum tumour necrosis factor-alpha is associated with poor health-related quality of life and depressive symptoms in patients with systemic lupus erythematosus. Lupus 22, 254–261 (2013).

    Article  CAS  PubMed  Google Scholar 

  156. Hur, J. et al. Identification of a novel role of T cells in postnatal vasculogenesis: characterization of endothelial progenitor cell colonies. Circulation 116, 1671–1682 (2007).

    Article  PubMed  Google Scholar 

  157. Miao, J. et al. Circulating angiogenic T cells and their subpopulations in patients with systemic lupus erythematosus. Mediators Inflamm. 2016, 2842143 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Zhao, P. et al. Circulating angiogenic T cells are increased in lupus nephritis patients. Med. Sci. Monit. 24, 5384–5390 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. López, P., Rodríguez-Carrio, J., Martínez-Zapico, A., Caminal-Montero, L. & Suarez, A. Senescent profile of angiogenic T cells from systemic lupus erythematosus patients. J. Leukoc. Biol. 99, 405–412 (2016).

    Article  PubMed  CAS  Google Scholar 

  160. Xu, M. G. et al. The functions of endothelial progenitor cells were significantly improved after treatment with intravenous immunoglobulin and aspirin in children with Kawasaki disease. Pediatr. Cardiol. 32, 455–460 (2011).

    Article  PubMed  Google Scholar 

  161. Pérez-Sánchez, C. et al. Early restoration of immune and vascular phenotypes in systemic lupus erythematosus and rheumatoid arthritis patients after B cell depletion. J. Cell Mol. Med. 23, 6308–6318 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Hsue, P. Y. et al. Depletion of B-cells with rituximab improves endothelial function and reduces inflammation among individuals with rheumatoid arthritis. J. Am. Heart Assoc. 3, e001267 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Morand, E. F. et al. Trial of anifrolumab in active systemic lupus erythematosus. N. Engl. J. Med. 382, 211–221 (2020).

    Article  CAS  PubMed  Google Scholar 

  164. Navarra, S. V. et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377, 721–731 (2011).

    Article  CAS  PubMed  Google Scholar 

  165. Furumoto, Y. et al. Tofacitinib ameliorates murine lupus and its associated vascular dysfunction. Arthritis Rheumatol. 69, 148–160 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Kaul, A. et al. Systemic lupus erythematosus. Nat. Rev. Dis. Prim. 2, 16039 (2016).

    Article  PubMed  Google Scholar 

  167. Svenungsson, E. et al. A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus. Ann. Rheum. Dis. 69, 834–840 (2010).

    Article  CAS  PubMed  Google Scholar 

  168. Huang, Z. et al. Vitamin D (1,25-(OH)2D3) improves endothelial progenitor cells function via enhanced no secretion in systemic lupus erythematosus. Cardiol. Res. Pract. 2020, 6802562 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Reynolds, J. A. et al. Vitamin D improves endothelial dysfunction and restores myeloid angiogenic cell function via reduced CXCL-10 expression in systemic lupus erythematosus. Sci. Rep. 6, 22341 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Sobrino, T., Blanco, M., Pérez-Mato, M., Rodríguez-Yáñez, M. & Castillo, J. Increased levels of circulating endothelial progenitor cells in patients with ischaemic stroke treated with statins during acute phase. Eur. J. Neurol. 19, 1539–1546 (2012).

    Article  CAS  PubMed  Google Scholar 

  171. Baran, Ç. et al. Effects of preoperative short term use of atorvastatin on endothelial progenitor cells after coronary surgery: a randomized, controlled trial. Stem Cell Rev. Rep. 8, 963–971 (2012).

    Article  CAS  PubMed  Google Scholar 

  172. Bahlmann, F. H. et al. Stimulation of endothelial progenitor cells: a new putative therapeutic effect of angiotensin II receptor antagonists. Hypertension 45, 526–529 (2005).

    Article  CAS  PubMed  Google Scholar 

  173. Cangiano, E. et al. ACE inhibition modulates endothelial apoptosis and renewal via endothelial progenitor cells in patients with acute coronary syndromes. Am. J. Cardiovasc. Drugs 11, 189–198 (2011).

    Article  CAS  PubMed  Google Scholar 

  174. França, C. N. et al. Endothelial progenitor cell mobilization and platelet microparticle release are influenced by clopidogrel plasma levels in stable coronary artery disease. Circ. J. 76, 729–736 (2012).

    Article  PubMed  CAS  Google Scholar 

  175. Chen, L. L. et al. Effects of gliclazide on endothelial function in patients with newly diagnosed type 2 diabetes. Eur. J. Pharmacol. 659, 296–301 (2011).

    Article  CAS  PubMed  Google Scholar 

  176. Fadini, G. P. et al. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha. Diabetes Care 33, 1607–1609 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Esposito, K. et al. Effects of pioglitazone versus metformin on circulating endothelial microparticles and progenitor cells in patients with newly diagnosed type 2 diabetes — a randomized controlled trial. Diabetes Obes. Metab. 13, 439–445 (2011).

    Article  CAS  PubMed  Google Scholar 

  178. Mok, C. C. et al. Long-term outcome of a randomised controlled trial comparing tacrolimus with mycophenolate mofetil as induction therapy for active lupus nephritis. Ann. Rheum. Dis. 79, 1070–1076 (2020).

    Article  PubMed  Google Scholar 

  179. Mok, C. C. et al. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. Ann. Rheum. Dis. 75, 30–36 (2016).

    Article  PubMed  Google Scholar 

  180. Yang, L. et al. Cyclosporin A suppresses proliferation of endothelial progenitor cells: involvement of nitric oxide synthase inhibition. Intern. Med. 47, 1457–1464 (2008).

    Article  PubMed  Google Scholar 

  181. Meyer, N., Brodowski, L., von Kaisenberg, C., Schröder-Heurich, B. & von Versen-Höynck, F. Cyclosporine A and tacrolimus induce functional impairment and inflammatory reactions in endothelial progenitor cells. Int. J. Mol. Sci. 22, 9696 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Ingram, D. A. et al. Vessel wall-derived endothelial cells rapidly proliferate because they contain a complete hierarchy of endothelial progenitor cells. Blood 105, 2783–2786 (2005).

    Article  CAS  PubMed  Google Scholar 

  183. Yoon, C. H. et al. Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases. Circulation 112, 1618–1627 (2005).

    Article  PubMed  Google Scholar 

  184. Schwartz, S. M. & Benditt, E. P. Clustering of replicating cells in aortic endothelium. Proc. Natl Acad. Sci. USA 73, 651–653 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Yoder, M. C. Is endothelium the origin of endothelial progenitor cells? Arterioscler. Thromb. Vasc. Biol. 30, 1094–1103 (2010).

    Article  CAS  PubMed  Google Scholar 

  186. Lin, R. Z., Hatch, A., Antontsev, V. G., Murthy, S. K. & Melero-Martin, J. M. Microfluidic capture of endothelial colony-forming cells from human adult peripheral blood: phenotypic and functional validation in vivo. Tissue Eng. C. Methods 21, 274–283 (2015).

    Article  CAS  Google Scholar 

  187. Karlsson, G., Sommarin, M. N. E. & Böiers, C. Defining the emerging blood system during development at single-cell resolution. Front. Cell Dev. Biol. 9, 660350 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Bian, Z. et al. Deciphering human macrophage development at single-cell resolution. Nature 582, 571–576 (2020).

    Article  CAS  PubMed  Google Scholar 

  189. Tselios, K., Sheane, B. J., Gladman, D. D. & Urowitz, M. B. Optimal monitoring for coronary heart disease risk in patients with systemic lupus erythematosus: a systematic review. J. Rheumatol. 43, 54–65 (2016).

    Article  CAS  PubMed  Google Scholar 

  190. Sella, E. M., Sato, E. I., Leite, W. A., Oliveira Filho, J. A. & Barbieri, A. Myocardial perfusion scintigraphy and coronary disease risk factors in systemic lupus erythematosus. Ann. Rheum. Dis. 62, 1066–1070 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Schanberg, L. E. et al. Premature atherosclerosis in pediatric systemic lupus erythematosus: risk factors for increased carotid intima-media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort. Arthritis Rheum. 60, 1496–1507 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Lu, X. et al. Patients with systemic lupus erythematosus face a high risk of cardiovascular disease: a systematic review and meta-analysis. Int. Immunopharmacol. 94, 107466 (2021).

    Article  CAS  PubMed  Google Scholar 

  193. Munguia-Realpozo, P. et al. Systemic lupus erythematosus and hypertension. Autoimmun. Rev. 18, 102371 (2019).

    Article  PubMed  Google Scholar 

  194. Molina, M. J. et al. Prevalence of systemic lupus erythematosus and associated comorbidities in Puerto Rico. J. Clin. Rheumatol. 13, 202–204 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Font, J. et al. Cardiovascular risk factors and the long-term outcome of lupus nephritis. QJM 94, 19–26 (2001).

    Article  CAS  PubMed  Google Scholar 

  196. Quinones, A., Lobach, I., Maduro, G. A. Jr., Smilowitz, N. R. & Reynolds, H. R. Diabetes and ischemic heart disease death in people age 25–54: a multiple-cause-of-death analysis based on over 400 000 deaths from 1990 to 2008 in New York City. Clin. Cardiol. 38, 114–120 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Yang, L. et al. Prevalence and correlation of conventional and lupus-specific risk factors for cardiovascular disease in Chinese systemic lupus erythematosus patients. J. Eur. Acad. Dermatol. Venereol. 26, 95–101 (2012).

    Article  CAS  PubMed  Google Scholar 

  198. Paolisso, G. et al. Evidence for peripheral impaired glucose handling in patients with connective tissue diseases. Metabolism 40, 902–907 (1991).

    Article  CAS  PubMed  Google Scholar 

  199. Zeng, Y. J. et al. Characteristics and risk factors for hyperglycemia in Chinese female patients with systemic lupus erythematosus. Lupus 19, 1344–1350 (2010).

    Article  PubMed  Google Scholar 

  200. Moroni, G. et al. Oxidative stress and homocysteine metabolism in patients with lupus nephritis. Lupus 19, 65–72 (2010).

    Article  CAS  PubMed  Google Scholar 

  201. Lazzerini, P. E. et al. Hyperhomocysteinemia: a cardiovascular risk factor in autoimmune diseases? Lupus 16, 852–862 (2007).

    Article  CAS  PubMed  Google Scholar 

  202. Bruce, I. N., Urowitz, M. B., Gladman, D. D., Ibañez, D. & Steiner, G. Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study. Arthritis Rheum. 48, 3159–3167 (2003).

    Article  PubMed  Google Scholar 

  203. Teh, P., Zakhary, B. & Sandhu, V. K. The impact of obesity on SLE disease activity: findings from the Southern California Lupus Registry (SCOLR). Clin. Rheumatol. 38, 597–600 (2019).

    Article  PubMed  Google Scholar 

  204. Tedeschi, S. K. et al. Obesity and the risk of systemic lupus erythematosus among women in the Nurses’ Health Studies. Semin. Arthritis Rheum. 47, 376–383 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Ghaussy, N. O., Sibbitt, W. L. Jr & Qualls, C. R. Cigarette smoking, alcohol consumption, and the risk of systemic lupus erythematosus: a case-control study. J. Rheumatol. 28, 2449–2453 (2001).

    CAS  PubMed  Google Scholar 

  206. Legge, A., Blanchard, C. & Hanly, J. G. Physical activity, sedentary behaviour and their associations with cardiovascular risk in systemic lupus erythematosus. Rheumatology 59, 1128–1136 (2020).

    Article  CAS  PubMed  Google Scholar 

  207. Mak, A. Physical exercise and systemic lupus erythematosus. Rheumatology 59, 921–922 (2020).

    Article  PubMed  Google Scholar 

  208. Manzi, S. et al. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum. 42, 51–60 (1999).

    Article  CAS  PubMed  Google Scholar 

  209. López-Pedrera, C. et al. Oxidative stress in the pathogenesis of atherothrombosis associated with anti-phospholipid syndrome and systemic lupus erythematosus: new therapeutic approaches. Rheumatology 55, 2096–2108 (2016).

    Article  PubMed  CAS  Google Scholar 

  210. Chorin, E. et al. Soluble ST2 and CXCL-10 may serve as biomarkers of subclinical diastolic dysfunction in SLE and correlate with disease activity and damage. Lupus 29, 1430–1437 (2020).

    Article  CAS  PubMed  Google Scholar 

  211. Sagar, D. et al. LOX-1: A potential driver of cardiovascular risk in SLE patients. PLoS One 15, e0229184 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Tripi, L. M. et al. Relationship of serum paraoxonase 1 activity and paraoxonase 1 genotype to risk of systemic lupus erythematosus. Arthritis Rheum. 54, 1928–1939 (2006).

    Article  CAS  PubMed  Google Scholar 

  213. Giannelou, M. & Mavragani, C. P. Cardiovascular disease in systemic lupus erythematosus: a comprehensive update. J. Autoimmun. 82, 1–12 (2017).

    Article  PubMed  Google Scholar 

  214. Apel, F., Zychlinsky, A. & Kenny, E. F. The role of neutrophil extracellular traps in rheumatic diseases. Nat. Rev. Rheumatol. 14, 467–475 (2018).

    Article  CAS  PubMed  Google Scholar 

  215. Al Gadban, M. M., Alwan, M. M., Smith, K. J. & Hammad, S. M. Accelerated vascular disease in systemic lupus erythematosus: role of macrophage. Clin. Immunol. 157, 133–144 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Parra, S. et al. Circulating FABP4 is a marker of metabolic and cardiovascular risk in SLE patients. Lupus 23, 245–254 (2014).

    Article  CAS  PubMed  Google Scholar 

  217. Nived, O. et al. Disease duration, age at diagnosis and organ damage are important factors for cardiovascular disease in SLE. Lupus Sci. Med. 7, e000398 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Kow, N. Y. & Mak, A. Costimulatory pathways: physiology and potential therapeutic manipulation in systemic lupus erythematosus. Clin. Dev. Immunol. 2013, 245928 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Ganjali, S., Shirmohammadi, L., Read, M. I. & Sahebkar, A. High-density lipoprotein functionality in systemic lupus erythematosus. Semin. Arthritis Rheum. 50, 769–775 (2020).

    Article  CAS  PubMed  Google Scholar 

  220. Frostegård, J. Autoimmunity, oxidized LDL and cardiovascular disease. Autoimmun. Rev. 1, 233–237 (2002).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank A-M. Fairhurst, for her expert contributions of flow cytometry evaluation of CD34+–CD133+–CD309+ circulating angiogenic cells, and L-H. Ling, and his team for their contributions of flow-mediated dilation measurement of our patients with SLE, and for his expert input into the information presented in Table 1.

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Authors and Affiliations

  1. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Anselm Mak

  2. Division of Rheumatology, University Medicine Cluster, National University Health System, Singapore, Singapore

    Anselm Mak

  3. Department of Reproductive Medicine, KK Women’s and Children’s Hospital, Singapore, Singapore

    Jerry Kok Yen Chan

  4. Academic Clinical Programme in Obstetrics and Gynaecology, Duke-NUS Medical School, Singapore, Singapore

    Jerry Kok Yen Chan

  5. Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Jerry Kok Yen Chan

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A.M. conceptualized the framework and content of the article; A.M. and J.K.Y.C. researched data for the article, made substantial contributions to discussions of the content, co-wrote the article, reviewed and edited the manuscript before submission.

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Correspondence to Anselm Mak.

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Competing interests

A.M. received consulting fees from Janssen and GlaxoSmithKline, and a research fund from GlaxoSmithKline for investigator-sponsored research through the GSK Supported Studies Programme (Proposal ID 10743). J.K.Y.C. received salary support from Singapore’s Ministry of Health’s National Medical Research Council (NMRC-CSA-SI-008/2016).

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Mak, A., Chan, J.K.Y. Endothelial function and endothelial progenitor cells in systemic lupus erythematosus. Nat Rev Rheumatol 18, 286–300 (2022). https://doi.org/10.1038/s41584-022-00770-y

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