Dysfunction of perivascular adipose tissue in metabolic syndrome and obesity: the role of the gasotransmitter hydrogen sulfide (review)

The development of novel strategies for diagnosing, treating, and preventing cardiovascular diseases (CVDs) linked to metabolic syndrome and obesity presents a significant challenge for the scientific community. There is a pressing need to identify effective compounds that target the underlying pathogenic mechanisms of these disorders. Increasing knowledge about the pathogenesis of CVDs has highlighted the crucial role of perivascular adipose tissue (PVAT) in maintaining cardiovascular homeostasis. PVAT is a metabolically active endocrine organ that plays a key role in regulating blood vessel tone, endothelial function, and the growth and proliferation of vascular smooth muscle cells. However, in metabolic disorders, there is a disruption in the functional activity of PVAT cellular components and an imbalance in the production of vasoactive substances, leading to the development and progression of CVDs. This review systematically examines the morphofunctional changes in PVAT associated with metabolic syndrome and obesity, emphasizes the dysfunction of PVAT as a key pathogenetic factor in cardiovascular disease, and evaluates the potential of hydrogen sulfide (H2S) produced by PVAT as a promising vasoregulatory agent based on existing data.

1. Vaduganathan M., Mensah G.A., Turco J.V., Fuster V., Roth G.A. The global burden of cardiovascular diseases and risk: A compass for future health. J. Am. Coll. Cardiol. 2022;80(25):2361–2371. DOI: 10.1016/j.jacc.2022.11.005.

2. Li X., Zhai Y., Zhao J., He H., Li Y., Liu Y. et al. Impact of metabolic syndrome and it’s components on prognosis in patients with cardiovascular diseases: A meta-analysis. Front. Cardiovasc. Med. 2021;8:704145. DOI: 10.3389/fcvm.2021.704145.

3. Hillock-Watling C., Gotlieb A.I. The pathobiology of perivascular adipose tissue (PVAT), the fourth layer of the blood vessel wall. Cardiovasc. Pathol. 2022;61:107459. DOI: 10.1016/j.carpath.2022.107459.

4. Bragina A., Rodionova Y., Druzhinina N., Suvorov A., Osadchiy K., Ishina T. et al. Relationship between perivascular adipose tissue and cardiovascular risk factors: A systematic review and meta-analysis. Metab. Syndr. Relat. Disord. 2024;22(1):1–14. DOI: 10.1089/met.2023.0097.

5. Chang L., Garcia-Barrio M.T., Chen Y.E. Perivascular adipose tissue regulates vascular function by targeting vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 2020;40(5):1094–1109. DOI: 10.1161/ATVBAHA.120.312464.

6. Adachi Y., Ueda K., Takimoto E. Perivascular adipose tissue in vascular pathologies-a novel therapeutic target for atherosclerotic disease? Front. Cardiovasc. Med. 2023;10:1151717. DOI: 10.3389/fcvm.2023.1151717.

7. Golas S., Berenyiova A., Majzunova M., Drobna M., Tuorkey M.J., Cacanyiova S. The vasoactive effect of perivascular adipose tissue and hydrogen sulfide in thoracic aortas of normotensive and spontaneously hypertensive rats. Biomolecules. 2022;12(3):457. DOI: 10.3390/biom12030457.

8. Costa R.M., Neves K.B., Tostes R.C., Lobato N.S. Perivascular adipose tissue as a relevant fat depot for cardiovascular risk in obesity. Front Physiol. 2018;9:253. DOI: 10.3389/fphys.2018.00253.

9. Stanek A., Brożyna-Tkaczyk K., Myśliński W. The role of obesity-induced perivascular adipose tissue (PVAT) dysfunction in vascular homeostasis. Nutrients. 2021;13(11):3843. DOI: 10.3390/nu13113843.

10. Ahmed A., Bibi A., Valoti M., Fusi F. Perivascular adipose tissue and vascular smooth muscle tone: Friends or foes? Cells. 2023;12(8):1196. DOI: 10.3390/cells12081196.

11. Man A.W.C., Zhou Y., Xia N., Li H. Perivascular adipose tissue oxidative stress in obesity. Antioxidants (Basel). 2023;12(8):1595. DOI: 10.3390/ antiox12081595.

12. Ramirez J.G., O’Malley E.J., Ho W.S.V. Pro-contractile effects of perivascular fat in health and disease. Br. J. Pharmacol. 2017;174(20):3482– 3495. DOI: 10.1111/bph.13767.

13. Haj-Yasein N.N., Berg O., Jernerén F., Refsum H., Nebb H.I., Dalen K.T. Cysteine deprivation prevents induction of peroxisome proliferator-activated receptor gamma-2 and adipose differentiation of 3T3-L1 cells. Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2017;1862(6):623–635. DOI: 10.1016/j.bbalip.2017.02.009.

14. Zaborska K.E., Wareing M., Edwards G., Austin C. Loss of anti-contractile effect of perivascular adipose tissue in offspring of obese rats. Int. J. Obes. (Lond.). 2016;40(8):1205–1214. DOI: 10.1038/ijo.2016.62.

15. Farias-Itao D.S., Pasqualucci C.A., de Andrade R.A., da Silva L.F.F., Yahagi-Estevam M., Lage S.H.G. et al. Macrophage polarization in the perivascular fat was associated with coronary atherosclerosis. J. Am. Heart. Assoc. 2022;11(6):e023274. DOI: 10.1161/JAHA.121.023274.

16. Cheng C.K., Ding H., Jiang M., Yin H., Gollasch M., Huang Y. Perivascular adipose tissue: Fine-tuner of vascular redox status and inflammation. Redox Biol. 2023;62:102683. DOI: 10.1016/j.redox.2023.102683.

17. Kumar R.K., Jin Y., Watts S.W., Rockwell C.E. Naïve, Regulatory, activated, and memory immune cells co-exist in PVATs that are comparable in density to non-PVAT fats in health. Front. Physiol. 2020;11:58. DOI: 10.3389/fphys.2020.00058.

18. Chen H.H., Li H.F., Tseng T.L., Lin H. Perivascular adipose tissue and adipocyte-derived exosomal miRNAs maintain vascular homeostasis. Heliyon. 2023;9(12):e22607. DOI: 10.1016/j.heliyon.2023.e22607.

19. Li X., Ballantyne L.L., Yu Y., Funk C.D. Perivascular adipose tissue-derived extracellular vesicle miR-221-3p mediates vascular remodeling. FASEB J. 2019;33(11):12704–12722. DOI: 10.1096/fj.201901548R.

20. Balbino-Silva C.S., Couto G.K., Lino C.A., de Oliveira-Silva T., Lunardon G., Huang Z.P. et al. miRNA-22 is involved in the aortic reactivity in physiological conditions and mediates obesity-induced perivascular adipose tissue dysfunction. Life Sci. 2023;316:121416. DOI: 10.1016/j.lfs.2023.121416.

21. Sun X., Lin J., Zhang Y., Kang S., Belkin N., Wara A.K. et al. MicroRNA-181b improves glucose homeostasis and insulin sensitivity by regulating endothelial function in white adipose tissue. Circ. Res. 2016;118(5):810–821. DOI: 10.1161/CIRCRESAHA.115.308166.

22. Nosalski R., Siedlinski M., Denby L., McGinnigle E., Nowak M., Cat A.N.D. et al. T-cell-derived miRNA-214 mediates perivascular fibrosis in hypertension. Circ. Res. 2020;126(8):988–1003. DOI: 10.1161/CIRCRESAHA.119.315428.

23. Essandoh K., Li Y., Huo J., Fan G.C. MiRNA-mediated macrophage polarization and its potential role in the regulation of inflammatory response. Shock. 2016;46(2):122–131. DOI: 10.1097/SHK.0000000000000604.

24. Runtsch M.C., Nelson M.C., Lee S.H., Voth W., Alexander M., Hu R. et al. Anti-inflammatory microRNA-146a protects mice from diet-induced metabolic disease. PLoS Genet. 2019;15(2):e1007970. DOI: 10.1371/journal.pgen.1007970.

25. Soci U.P.R., Cavalcante B.R.R., Improta-Caria A.C., Roever L. The epigenetic role of MiRNAs in endocrine crosstalk between the cardiovascular system and adipose tissue: A bidirectional view. Front. Cell Dev. Biol. 2022;10:910884. DOI: 10.3389/fcell.2022.910884.

26. Hendriks K.D., Maassen H., van Dijk P.R., Henning R.H., van Goor H., Hillebrands J.L. Gasotransmitters in health and disease: a mitochondria-centered view. Curr. Opin. Pharmacol. 2019;45:87–93. DOI: 10.1016/j.coph.2019.07.001.

27. Comas F., Moreno-Navarrete J.M. The impact of H2 S on obesity-associated metabolic disturbances. Antioxidants (Basel). 2021;10(5):633. DOI: 10.3390/antiox10050633.

28. Zhang Y.X., Jing M.R., Cai C.B., Zhu S.G., Zhang C.J., Wang Q.M. et al. Role of hydrogen sulphide in physiological and pathological angiogenesis. Cell Prolif. 2023;56(3):e13374. DOI: 10.1111/cpr.13374.

29. Yakovlev A.V., Kurmasheva E.D., Giniatullin R., Khalilov I., Sitdikova G.F. Hydrogen sulfide inhibits giant depolarizing potentials and abolishes epileptiform activity of neonatal rat hippocampal slices. Neuroscience. 2017;340:153–165. DOI: 10.1016/j.neuroscience.2016.10.051.

30. Panthi S., Manandhar S., Gautam K. Hydrogen sulfide, nitric oxide, and neurodegenerative disorders. Transl. Neurodegener. 2018;7:3. DOI: 10.1186/s40035-018-0108-x.

31. Bełtowski J., Wiórkowski K. Role of hydrogen sulfide and polysulfides in the regulation of lipolysis in the adipose tissue: Possible implications for the pathogenesis of metabolic syndrome. Int. J. Mol. Sci. 2022;23(3):1346. DOI: 10.3390/ijms23031346.

32. Hine C., Ponti A.K., Cáliz-Molina M.Á., Martín-Montalvo A. H2 S serves as the immunoregulatory essence of apoptotic cell death. Cell Metab. 2024;36(1):3–5. DOI: 10.1016/j.cmet.2023.12.006.

33. Testai L., Citi V., Martelli A., Brogi S., Calderone V. Role of hydrogen sul fide in cardiovascular ageing. Pharmacol. Res. 2020;160:105125. DOI: 10.1016/j.phrs.2020.105125.

34. Filipovic M.R., Zivanovic J., Alvarez B., Banerjee R. Chemical biology of H2 S signaling through persulfidation. Chem. Rev. 2018;118(3):1253– 1337. DOI: 10.1021/acs.chemrev.7b00205.

35. Cirino G., Szabo C., Papapetropoulos A. Physiological roles of hydrogen sulfide in mammalian cells, tissues, and organs. Physiol. Rev. 2023;103(1):31–276. DOI: 10.1152/physrev.00028.2021.

36. Kowalczyk-Bołtuć J., Wiórkowski K., Bełtowski J. Effect of exogenous hydrogen sulfide and polysulfide donors on insulin sensitivity of the adipose tissue. Biomolecules. 2022;12(5):646. DOI: 10.3390/biom12050646.

37. Tian Z., Deng N.H., Zhou Z.X., Ren Z., Xiong W.H., Jiang Z.S. The role of adipose tissue-derived hydrogen sulfide in inhibiting atherosclerosis. Nitric Oxide. 2022;127:18–25. DOI: 10.1016/j.niox.2022.07.001.

38. Ding Y., Wang H., Geng B., Xu G. Sulfhydration of perilipin 1 is involved in the inhibitory effects of cystathionine gamma lyase / hydrogen sulfide on adipocyte lipolysis. Biochem. Biophys. Res. Commun. 2020;521(3):786–790. DOI: 10.1016/j.bbrc.2019.10.192.

39. Lv B., Chen S., Tang C., Jin H., Du J., Huang Y. Hydrogen sulfide and vascular regulation – An update. J. Adv. Res. 2020;27:85–97. DOI: 10.1016/j.jare.2020.05.007.

40. Cacanyiova S., Majzunova M., Golas S., Berenyiova A. The role of perivascular adipose tissue and endogenous hydrogen sulfide in vasoactive responses of isolated mesenteric arteries in normotensive and spontaneously hypertensive rats. J. Physiol. Pharmacol. 2019;70(2). DOI: 10.26402/jpp.2019.2.13.

41. Bełtowski J., Guranowski A., Jamroz-Wiśniewska A., Wolski A., Hałas K. Hydrogen-sulfide-mediated vasodilatory effect of nucleoside 5’-monophosphorothioates in perivascular adipose tissue. Can. J. Physiol. Pharmacol. 2015;93(7):585–595. DOI: 10.1139/cjpp-2014-0543.

42. Revenko O., Pavlovskiy Y., Savytska M., Yashchenko A., Kovalyshyn V., Chelpanova I. et al. Hydrogen sulfide prevents mesenteric adipose tissue damage, endothelial dysfunction, and redox imbalance from high fructose diet-induced injury in aged rats. Front. Pharmacol. 2021;12:693100. DOI: 10.3389/fphar.2021.693100.

43. Candela J., Wang R., White C. Microvascular endothelial dysfunction in obesity is driven by macrophage-dependent hydrogen sulfide depletion. Arterioscler. Thromb. Vasc. Biol. 2017;37(5):889–899. DOI: 10.1161/ATVBAHA.117.309138.

44. Kumar A., Bhatia M. Role of hydrogen sulfide, substance P and adhesion molecules in acute pancreatitis. Int. J. Mol. Sci. 2021;22(22):12136. DOI: 10.3390/ijms222212136.

45. Tian D., Teng X., Jin S., Chen Y., Xue H., Xiao L. et al. Endogenous hydrogen sulfide improves vascular remodeling through PPARδ/SOCS3 signaling. J. Adv. Res. 2020;27:115–125. DOI: 10.1016/j.jare.2020.06.005.

46. Zhu J., Yang G. H2 S signaling and extracellular matrix remodeling in cardiovascular diseases: A tale of tense relationship. Nitric Oxide. 2021;116:14–26. DOI: 10.1016/j.niox.2021.08.004.

47. Yue L.M., Gao Y.M., Han B.H. Evaluation on the effect of hydrogen sulfide on the NLRP3 signaling pathway and its involvement in the pathogenesis of atherosclerosis. J. Cell Biochem. 2019;120(1):481–492. DOI: 10.1002/jcb.27404.

48. Pan Z., Wang J., Xu M., Chen S., Li X., Sun A. et al. Hydrogen sulfide protects against high glucose induced lipid metabolic disturbances in 3T3 L1 adipocytes via the AMPK signaling pathway. Mol. Med. Rep. 2019;20(5):4119–4124. DOI: 10.3892/mmr.2019.10685.

49. Gomez C.B., de la Cruz S.H., Medina-Terol G.J., Beltran-Ornelas J.H., Sánchez-López A., Silva-Velasco D.L. et al. Chronic administration of NaHS and L-Cysteine restores cardiovascular changes induced by highfat diet in rats. Eur. J. Pharmacol. 2019;863:172707. DOI: 10.1016/j.ejphar.2019.172707.

50. Tong Y., Zuo Z., Li X., Li M., Wang Z., Guo X. et al. Protective role of perivascular adipose tissue in the cardiovascular system. Front. Endocrinol. (Lausanne). 2023;14:1296778. DOI: 10.3389/fendo.2023.1296778.