Dynamics of indicators of endothelial dysfunction in children with obesity

Introduction. Constitutionally exogenous obesity (CEO) belongs to a number of significant medical and social problems of the modern world, assumes epidemic proportions and leads among alimentary-dependent pathology in children.

The aim of the work was to determine changes in indicators of endothelial dysfunction (ED) in children of different age with obesity of various severity.

Materials and methods. One hundred twenty six children aged of 6 to 17 years were comprehensively examined, data on changes in the serum content of ED mediators in CEOs grade 1–3 were presented by quantitative determination of nitric oxide, endothelin-1, leptin, homocysteine, intercellular adhesion molecules and vascular cell adhesion-1, tissue-type plasminogen activator inhibitor antigen, Willebrand factor and his antigen.

Results. The regularities of changes in the concentrations of these compounds in the blood depending on the age of patients and the degree of obesity, which reflect the functional state of the endothelial system and can serve as criteria for the severity of ED requiring adequate and timely correction in children, have been established.

Conclusion. Indicators of endothelial dysfunction can serve as criteria for its severity, their detection will allow optimizing early diagnosis and determining the amount of timely therapy.

Contribution:
Smirnov I.E., Kucherenko A.G. — concept and design of the study;
Kucherenko A.G., Postnikova E.V., Smirnova G.I. — collection of material;
Kucherenko A.G., Smirnov I.E. — statistical processing;
Smirnov I.E. — writing of the text;
Fisenko A.P. — editing.
All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Acknowledgment. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: April 25, 2022
Accepted: April 26, 2022
Published: May 07, 2022

1. Tagi V.M., Chiarelli F. Obesity and insulin resistance in children. Curr. Opin. Pediatr. 2020; 32(4): 582–8. https://doi.org/10.1097/MOP.0000000000000913

2. Staiano A.E., Katzmarzyk P.T. Increases in adiposity among children and adolescents over time: Moving beyond BMI. Am. J. Clin. Nutr. 2021; 114(4): 1275–6. https://doi.org/10.1093/ajcn/nqab265

3. Stierman B., Ogden C.L., Yanovski J.A., Martin C.B., Sarafrazi N., Hales C.M. Changes in adiposity among children and adolescents in the United States, 1999-2006 to 2011-2018. Am. J. Clin. Nutr. 2021; 114(4): 1495–504. https://doi.org/10.1093/ajcn/nqab237

4. Twig G., Yaniv G., Levine H., Leiba A., Goldberger N., Derazne E., et al. Body-mass index in 2.3 million adolescents and cardiovascular death in adulthood. N. Engl. J. Med. 2016; 374(25): 2430–40. https://doi.org/10.1056/nejmoa1503840

5. Hruska V., Ambrose T., Darlington G., Ma D.W.L., Haines J., Buchholz A.C. Stress is associated with adiposity in parents of young children. Obesity (Silver Spring). 2020; 28(3): 655–9. https://doi.org/10.1002/oby.22710

6. Agarwal A.K. Spice up your life: adipose tissue and inflammation. J. Lipids. 2014; 2014: 182575. https://doi.org/10.1155/2014/182575

7. Koenen M., Hill M.A., Cohen P., Sowers J.R. Obesity, adipose tissue and vascular dysfunction. Circ. Res. 2021; 128(7): 951–68. https://doi.org/10.1161/circresaha.121.318093

8. Kereliuk S.M., Dolinsky V.W. Recent experimental studies of maternal obesity, diabetes during pregnancy and the developmental origins of cardiovascular disease. Int. J. Mol. Sci. 2022; 23(8): 4467. https://doi.org/10.3390/ijms23084467

9. Foster B.A., Reynolds K., Callejo-Black A., Polensek N., Weill B.C. Weight outcomes in children with developmental disabilities from a multidisciplinary clinic. Res. Dev. Disabil. 2021; 108: 103809. https://doi.org/10.1016/j.ridd.2020.103809

10. El-Yazbi A.F., Oudit G.Y. Adipose biology, cardiovascular, and cardiometabolic disease: novel insights and new targets for intervention. Clin. Sci. (Lond). 2020; 134(12): 1473–4. https://doi.org/10.1042/CS20200816

11. Kessler Ch. Pathophysiology of Obesity. Nurs. Clin. North Am. 2021; 56(4): 465–78. https://doi.org/10.1016/j.cnur.2021.08.001

12. Tutel’yan V.A., Baturin A.K., Kon’ I.Ya. The prevalence of obesity and overweight among the Russian children’s population: a multicentre study. Pediatriya. Zhurnal im. G.N. Speranskogo. 2014; 93(5): 28–31. (in Russian)

13. Martynova I.N., Vinyarskaya I.V., Terletskaya R.N., Postnikova E.V., Frolova G.S. Questions of true incidence and prevalence of obesity in children and adolescents. Rossiyskiy pediatricheskiy zhurnal. 2016; 19(1): 23–8. https://doi.org/10.18821/1560-9561-2016-19(1)-23-28 (in Russian)

14. Whittle A.J., Jiang M., Peirce V., Relat J., Virtue S., Ebinuma H., et al. Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans. Nat. Commun. 2015; 6: 8951. https://doi.org/10.1038/ncomms9951

15. Pigeyre M., Yazdi F.T., Kaur Y., Meyre D. Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity. Clin. Sci. (Lond.). 2016; 130(12): 943–86. https://doi.org/10.1042/cs20160136

16. Belyaeva I.A., Bombardirova E.P., Smirnov I.E., Kharitonova N.A. Neurotrophic aspects of feeding preterm infants. Rossiyskiy pediatricheskiy zhurnal. 2015; 18(5): 30–7. (in Russian)

17. Ugwoke C.K., Cvetko E., Umek N. Skeletal muscle microvascular dysfunction in obesity-related insulin resistance: pathophysiological mechanisms and therapeutic perspectives. Int. J. Mol. Sci. 2022; 23(2): 847. https://doi.org/10.3390/ijms23020847

18. Li M., Qian M., Kyler K., Xu J. Adipose tissue-endothelial cell interactions in obesity-induced endothelial dysfunction. Front. Cardiovasc. Med. 2021; 8: 681581. https://doi.org/10.3389/fcvm.2021.681581

19. Altabas V., Biloš L.S.K. The role of endothelial progenitor cells in atherosclerosis and impact of anti-lipemic treatments on endothelial repair. Int. J. Mol. Sci. 2022; 23(5): 2663. https://doi.org/10.3390/ijms23052663

20. Skvortsova V.A., Khadzhieva M.V., Borovik T.E., Bushueva T.V., Smirnov I.E., Mayanskiy N.A., et al. Adipokines and hormones in children of primary school age with normal and excess body weight. Rossiyskiy pediatricheskiy zhurnal. 2019; 22(3): 137–43. https://doi.org/10.18821/1560-9561-2019-22-3-137-143 (in Russian)

21. Kawai T., Autieri M.V., Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am. J. Physiol. Cell Physiol. 2021; 320(3): C375–91. https://doi.org/10.1152/ajpcell.00379.2020

22. Zhang Z., Adamo K.B., Ogden N., Goldfield G.S., Okely A.D., Kuzik N., et al. Associations between sleep duration, adiposity indicators, and cognitive development in young children. Sleep Med. 2021; 82: 54–60. https://doi.org/10.1016/j.sleep.2021.03.037

23. Martinez-Santibañez G., Lumeng C.N. Macrophages and the regulation of adipose tissue remodeling. Annu. Rev. Nutr. 2014; 34: 57–76. https://doi.org/10.1146/annurev-nutr-071812-161113

24. Lemoine A.Y., Ledoux S., Larger E. Adipose tissue angiogenesis in obesity. Thromb. Haemost. 2013; 110(4): 661–8. https://doi.org/10.1160/TH13-01-0073

25. Marcelin G., Silveira A.L.M., Martins L.B., Ferreira A.V., Clément K. Deciphering the cellular interplays underlying obesity-induced adipose tissue fibrosis. J. Clin. Invest. 2019; 129(10): 4032–40. https://doi.org/10.1172/JCI129192

26. Crewe C., An Y.A., Scherer P.E. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J. Clin. Invest. 2017; 127(1): 74–82. https://doi.org/10.1172/JCI88883

27. Pellegrinelli V., Rodriguez-Cuenca S., Rouault C., Figueroa-Juarez E., Schilbert H., Virtue S., et al. Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance. Nat. Metab. 2022; 4(4): 476–94. https://doi.org/10.1038/s42255-022-00561-5

28. Boutagy N.E., Singh A.K., Sessa W.C. Targeting the vasculature in cardiometabolic disease. J. Clin. Invest. 2022; 132(6): e148556. https://doi.org/10.1172/JCI148556

29. Cyr A.R., Huckaby L.V., Shiva S.S., Zuckerbraun B.S. Nitric oxide and endothelial dysfunction. Crit. Care. Clin. 2020; 36(2): 307–21. https://doi.org/10.1016/j.ccc.2019.12.009

30. Müller M.M., Griesmacher A. Markers of endothelial dysfunction. Clin. Chem. Lab. Med. 2000; 38(2): 77–85. https://doi.org/10.1515/CCLM.2000.013

31. Taneja G., Sud A., Pendse N., Panigrahi B., Kumar A., Sharma A.K. Nano-medicine and vascular endothelial dysfunction: options and delivery strategies. Cardiovasc. Toxicol. 2019; 19(1): 1–12. https://doi.org/10.1007/s12012-018-9491-x

32. Maggio A.B.R., Farpour-Lambert N.J., Aggoun Y., Galan K., Montecucco F., Mach F., et al. Serum cardiovascular risk biomarkers in pre-pubertal obese children. Eur. J. Clin. Invest. 2018; 48(9): e12995. https://doi.org/10.1111/eci.12995

33. Salamt N., Muhajir M., Aminuddin A., Ugusman A. The effects of exercise on vascular markers and C-reactive protein among obese children and adolescents: An evidence-based review. Bosn. J. Basic Med. Sci. 2020; 20(2): 149–56. https://doi.org/10.17305/bjbms.2019.4345

34. Genovesi S., Parati G. Cardiovascular risk in children: focus on pathophysiological aspects. Int. J. Mol. Sci. 2020; 21(18): 6612. https://doi.org/10.3390/ijms21186612

35. Cote A.T., Harris K.C., Panagiotopoulos C., Sandor G.G., Devlin A.M. Childhood obesity and cardiovascular dysfunction. J. Am. Coll. Cardiol. 2013; 62(15): 1309–19. https://doi.org/10.1016/j.jacc.2013.07.042

36. Lo M.H., Lin I.C., Lu P.C., Huang C.F., Chien S.J., Hsieh K.S., et al. Evaluation of endothelial dysfunction, endothelial plasma markers, and traditional metabolic parameters in children with adiposity. J. Formos. Med. Assoc. 2019; 118(Pt. 1): 83–91. https://doi.org/10.1016/j.jfma.2018.01.007

37. Rastogi S., Rastogi D. The epidemiology and mechanisms of lifetime cardiopulmonary morbidities associated with pre-pregnancy obesity and excessive gestational weight gain. Front. Cardiovasc. Med. 2022; 9: 844905. https://doi.org/10.3389/fcvm.2022.844905

38. Niu Y., Zhao X., He H., Mao X., Sheng J., Zou J., et al. The effect of different adiposity factors on insulin resistance in obese children and adolescents. Clin. Endocrinol. (Oxf). 2021; 94(6): 949–55. https://doi.org/10.1111/cen.14435

39. Kwaifa I.K., Bahari H., Yong Y.K., Noor S.M. Endothelial dysfunction in obesity-induced inflammation: molecular mechanisms and clinical implications. Biomolecules. 2020; 10(2): 291. https://doi.org/10.3390/biom10020291

40. Adelantado-Renau M., Esteban-Cornejo I., Mora-Gonzalez J., Plaza-Florido A., Rodriguez-Ayllon M., Maldonado J., et al. Neurotrophic factors and brain health in children with overweight and obesity: The role of cardiorespiratory fitness. Eur. J. Sport Sci. 2022; 1–12. https://doi.org/10.1080/17461391.2022.2044912

41. Bruyndonckx L., Hoymans V.Y., Van Craenenbroeck A.H., Vissers D.K., Vrints C.J., Ramet J., et al. Assessment of endothelial dysfunction in childhood obesity and clinical use. Oxid. Med. Cell. Longev. 2013; 2013: 174782. https://doi.org/10.1155/2013/174782

42. Xie Y., Liu L. Role of Chemerin/ChemR23 axis as an emerging therapeutic perspective on obesity-related vascular dysfunction. J. Transl. Med. 2022; 20(1): 141. https://doi.org/10.1186/s12967-021-03220-7

43. Vanhoutte P.M. Endothelial dysfunction in obesity. Ann. Pharm. Fr. 2013; 71(1): 42–50. https://doi.org/10.1016/j.pharma.2012.10.003

44. Balta S. Endothelial dysfunction and inflammatory markers of vascular disease. Curr. Vasc. Pharmacol. 2021; 19(3): 243–9. https://doi.org/10.2174/1570161118666200421142542

45. Phan H.T.T., Borca F., Cable D., Batchelor J., Davies J.H., Ennis S. Automated data cleaning of paediatric anthropometric data from longitudinal electronic health records: protocol and application to a large patient cohort. Sci. Rep. 2020; 10(1): 10164. https://doi.org/10.1038/s41598-020-66925-7

46. Peterkova V.A., Bezlepkina O.B., Bolotova N.V., Bogova E.A., Vasyukova O.V., Girsh Ya.V., et al. Clinical guidelines «Obesity in children». Problemy endokrinologii. 2021; 67(5): 67–83. https://doi.org/10.14341/probl12802 (in Russian)

47. Godo S., Shimokawa H. Endothelial Functions. Arterioscler. Thromb. Vasc. Biol. 2017; 37(9): e108–14. https://doi.org/10.1161/atvbaha.117.309813

48. Adamczyk A., Matuszyk E., Radwan B., Rocchetti S., Chlopicki S., Baranska M. Toward raman subcellular imaging of endothelial dysfunction. J. Med. Chem. 2021; 64(8): 4396–409. https://doi.org/10.1021/acs.jmedchem.1c00051

49. Ugusman A., Kumar J., Aminuddin A. Endothelial function and dysfunction: impact of sodium-glucose cotransporter 2 inhibitors. Pharmacol. Ther. 2021; 224: 107832. https://doi.org/10.1016/j.pharmthera.2021.107832

50. Clyne A.M. Endothelial response to glucose: dysfunction, metabolism, and transport. Biochem. Soc. Trans. 2021; 49(1): 313–25. https://doi.org/10.1042/bst20200611

51. Virdis A. Endothelial dysfunction in obesity: role of inflammation. High Blood Press. Cardiovasc. Prev. 2016; 23(2): 83–5. https://doi.org/10.1007/s40292-016-0133-8

52. Rana M.N., Neeland I.J. Adipose tissue inflammation and cardiovascular disease: an update. Curr. Diab. Rep. 2022; 22(1): 27–37. https://doi.org/10.1007/s11892-021-01446-9

53. Incalza M.A., D’Oria R., Natalicchio A., Perrini S., Laviola L., Giorgino F. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascul. Pharmacol. 2018; 100: 1–19. https://doi.org/10.1016/j.vph.2017.05.005

54. Ait-Aissa K., Nguyen Q.M., Gabani M., Kassan A., Kumar S., Choi S.K., et al. MicroRNAs and obesity-induced endothelial dysfunction: key paradigms in molecular therapy. Cardiovasc. Diabetol. 2020; 19(1): 136. https://doi.org/10.1186/s12933-020-01107-3

55. Perdoncin M., Konrad A., Wyner J.R., Lohana S., Pillai S.S., Pereira D.G., et al. A review of miRNAs as biomarkers and effect of dietary modulation in obesity associated cognitive decline and neurodegenerative disorders. Front. Mol. Neurosci. 2021; 14: 756499. https://doi.org/10.3389/fnmol.2021.756499

56. Genovesi S., Giussani M., Orlando A., Lieti G., Viazzi F., Parati G. Relationship between endothelin and nitric oxide pathways in the onset and maintenance of hypertension in children and adolescents. Pediatr. Nephrol. 2022; 37(3): 537–45. https://doi.org/10.1007/s00467-021-05144-2

57. Selvaraju V., Ayine P., Fadamiro M., Babu J.R., Brown M., Geetha T. Urinary biomarkers of inflammation and oxidative stress are elevated in obese children and correlate with a marker of endothelial dysfunction. Oxid. Med. Cell Longev. 2019; 2019: 9604740. https://doi.org/10.1155/2019/9604740

58. Engin A. Endothelial dysfunction in obesity. Adv. Exp. Med. Biol. 2017; 960: 345–79. https://doi.org/10.1007/978-3-319-48382-5_15

59. Sioen I., Lust E., De Henauw S., Moreno L.A., Jiménez-Pavón D. Associations between body composition and bone health in children and adolescents: a systematic review. Calcif. Tissue. Int. 2016; 99(6): 557–77. https://doi.org/10.1007/s00223-016-0183-x

60. Tint M.T., Michael N., Sadananthan S.A., Huang J.Y., Khoo C.M., Godfrey K.M., et al. Brown adipose tissue, adiposity, and metabolic profile in preschool children. J. Clin. Endocrinol. Metab. 2021; 106(10): 2901–14. https://doi.org/10.1210/clinem/dgab447

61. King R.J., Ajjan R.A. Vascular risk in obesity: Facts, misconceptions and the unknown. Diab. Vasc. Dis. Res. 2017; 14(1): 2–13. https://doi.org/10.1177/1479164116675488

62. Jimenez M.T., Michieletto M.F., Henao-Mejia J. A new perspective on mesenchymal-immune interactions in adipose tissue. Trends. Immunol. 2021; 42(5): 375–88. https://doi.org/10.1016/j.it.2021.03.001

63. Kozhevnikova O.V., Smirnov I.E. Risk factors for cardiovascular pathology in children: the properties of blood vessels and atherosclerosis. Rossiyskiy pediatricheskiy zhurnal. 2015; 18(4): 36–42. (in Russian)

64. Lawler K., Huang-Doran I., Sonoyama T., Collet T.H., Keogh J.M., Henning E., et al. Leptin-mediated changes in the human metabolome. J. Clin. Endocrinol. Metab. 2020; 105(8): 2541–52. https://doi.org/10.1210/clinem/dgaa251

65. Obradovic M., Sudar-Milovanovic E., Soskic S., Essack M., Arya S., Stewart A.J., et al. Leptin and obesity: role and clinical implication. Front. Endocrinol. (Lausanne). 2021; 12: 585887. https://doi.org/10.3389/fendo.2021.585887

66. Seth M., Biswas R., Ganguly S., Chakrabarti N., Chaudhuri A.G. Leptin and obesity. Physiol. Int. 2020; 107(4): 455–68. https://doi.org/10.1556/2060.2020.00038

67. Zhao S., Kusminski C.M., Elmquist J.K., Scherer P.E. Leptin: less is more. Diabetes. 2020; 69(5): 823–9. https://doi.org/10.2337/dbi19-0018

68. Genchi V.A., D’Oria R., Palma G., Caccioppoli C., Cignarelli A., Natalicchio A., et al. Impaired leptin signalling in obesity: is leptin a new thermolipokine? Int. J. Mol. Sci. 2021; 22(12): 6445. https://doi.org/10.3390/ijms22126445

69. La Cava A. Leptin in inflammation and autoimmunity. Cytokine. 2017; 98: 51–8. https://doi.org/10.1016/j.cyto.2016.10.011

70. Peng J., Yin L., Wang X. Central and peripheral leptin resistance in obesity and improvements of exercise. Horm. Behav. 2021; 133: 105006. https://doi.org/10.1016/j.yhbeh.2021.105006

71. Enriori P.J., Sinnayah P., Simonds S.E., Garcia Rudaz C., Cowley M.A. Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance. J. Neurosci. 2011; 31(34): 12189–97. https://doi.org/10.1523/jneurosci.2336-11.2011

72. Russo B., Menduni M., Borboni P., Picconi F., Frontoni S. Autonomic nervous system in obesity and insulin-resistance-the complex interplay between leptin and central nervous system. Int. J. Mol. Sci. 2021; 22(10): 5187. https://doi.org/10.3390/ijms22105187

73. Hernández Morante J.J., Díaz Soler I., Muñoz J.S.G., Sánchez H.P., Barberá Ortega M.D.C., Martínez C.M., et al. Moderate weight loss modifies leptin and ghrelin synthesis rhythms but not the subjective sensations of appetite in obesity patients. Nutrients. 2020; 12(4): 916. https://doi.org/10.3390/nu12040916

74. Mark A.L., Correia M.L.G., Rahmouni K., Haynes W.G. Selective leptin resistance: a new concept in leptin physiology with cardiovascular implications. J. Hypertens. 2002; 20(7): 1245–50. https://doi.org/10.1097/00004872-200207000-00001

75. Lu S.C., Akanji A.O. Leptin, obesity, and hypertension: a review of pathogenetic mechanisms. Metab. Syndr. Relat. Disord. 2020; 18(9): 399–405. https://doi.org/10.1089/met.2020.0065

76. Azzini E., Ruggeri S., Polito A. Homocysteine: its possible emerging role in at-risk population groups. Int. J. Mol. Sci. 2020; 21(4): 1421. https://doi.org/10.3390/ijms21041421

77. Wang J., You D., Wang H., Yang Y., Zhang D., Lv J., et al. Association between homocysteine and obesity: A meta-analysis. J. Evid. Based. Med. 2021; 14(3): 208–17. https://doi.org/10.1111/jebm.12412

78. Laha A., Majumder A., Singh M., Tyagi S.C. Connecting homocysteine and obesity through pyroptosis, gut microbiome, epigenetics, peroxisome proliferator-activated receptor gamma, and zinc finger protein 407. Can. J. Physiol. Pharmacol. 2018; 96(10): 971–6. https://doi.org/10.1139/cjpp-2018-0037

79. Smirnova G.I., Mankute G.R. Intestinal microbiota and atopic dermatitis in children. Rossiyskiy pediatricheskiy zhurnal. 2015; 18(6): 46–53. (in Russian)

80. Yuan X., Chen R., McCormick K.L., Zhang Y., Lin X., Yang X. The role of the gut microbiota on the metabolic status of obese children. Microb. Cell. Fact. 2021; 20(1): 53. https://doi.org/10.1186/s12934-021-01548-9

81. Valls M.D., Soldado M., Arasa J., Perez-Aso M., Williams A.J., Cronstein B.N., et al. Annexin A2-mediated plasminogen activation in endothelial cells contributes to the proangiogenic effect of adenosine A2A receptors. Front. Pharmacol. 2021; 12: 654104. https://doi.org/10.3389/fphar.2021.654104

82. Zheng Z., Nakamura K., Gershbaum S., Wang X., Thomas S., Bessler M., et al. Interacting hepatic PAI-1/tPA gene regulatory pathways influence impaired fibrinolysis severity in obesity. J. Clin. Invest. 2020; 130(8): 4348–59. https://doi.org/10.1172/JCI135919