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Remote Effects of Transplanted Perivascular Adipose Tissue on Endothelial Function and Atherosclerosis

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Abstract

Purpose

Perivascular adipose tissue (PVAT) surrounds the arterial adventitia and plays an important role in vascular homeostasis. PVAT expands in obesity, and inflamed PVAT can locally promote endothelial dysfunction and atherosclerosis. Here, using adipose tissue transplantation, we tested the hypothesis that expansion of PVAT can also remotely exacerbate vascular disease.

Methods

Fifty milligrams of abdominal aortic PVAT was isolated from high-fat diet (HFD)-fed wild-type mice and transplanted onto the abdominal aorta of lean LDL receptor knockout mice. Subcutaneous and visceral adipose tissues were used as controls. After HFD feeding for 10 weeks, body weight, glucose/insulin sensitivity, and lipid levels were measured. Adipocytokine gene expression was assessed in the transplanted adipose tissues, and the thoracic aorta was harvested to quantify atherosclerotic lesions by Oil-Red O staining and to assess vasorelaxation by wire myography.

Results

PVAT transplantation did not influence body weight, fat composition, lipid levels, or glucose/insulin sensitivity. However, as compared with controls, transplantation of PVAT onto the abdominal aorta increased thoracic aortic atherosclerosis. Furthermore, PVAT transplantation onto the abdominal aorta inhibited endothelium-dependent relaxation in the thoracic aorta. MCP-1 and TNF-α expression was elevated, while adiponectin expression was reduced, in the transplanted PVAT tissue, suggesting augmented inflammation as a potential mechanism for the remote vascular effects of transplanted PVAT.

Conclusions

These data suggest that PVAT expansion and inflammation in obesity can remotely induce endothelial dysfunction and augment atherosclerosis. Identifying the underlying mechanisms may lead to novel approaches for risk assessment and treatment of obesity-related vascular disease.

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References

  1. Verhagen SN, Visseren FL. Perivascular adipose tissue as a cause of atherosclerosis. Atherosclerosis. 2011;214(1):3–10.

    Article  CAS  Google Scholar 

  2. Fitzgibbons TP, Czech MP. Epicardial and perivascular adipose tissues and their influence on cardiovascular disease: basic mechanisms and clinical associations. J Am Heart Assoc. 2014;3(2):e000582.

    Article  Google Scholar 

  3. Cai XJ, Li CJ, Chen L, Rong YY, Zhang Y, Zhang M. A hypothesis: adiponectin mediates anti-atherosclerosis via adventitia-AMPK-iNOS pathway. Med Hypotheses. 2008;70(5):1044–7.

    Article  CAS  Google Scholar 

  4. Aghamohammadzadeh R, Unwin RD, Greenstein AS, Heagerty AM. Effects of obesity on perivascular adipose tissue vasorelaxant function: nitric oxide, inflammation and elevated systemic blood pressure. J Vasc Res. 2015;52(5):299–305.

    Article  CAS  Google Scholar 

  5. Takaoka M, Nagata D, Kihara S, Shimomura I, Kimura Y, Tabata Y, et al. Periadventitial adipose tissue plays a critical role in vascular remodeling. Circ Res. 2009;105(9):906–11.

    Article  CAS  Google Scholar 

  6. Tanaka K, Komuro I, Sata M. Vascular cells originating from perivascular adipose tissue contribute to vasa vasorum neovascularization in atherosclerosis. Circulation. 2015;132(Suppl_3):A14910.

  7. Police SB, Thatcher SE, Charnigo R, Daugherty A, Cassis LA. Obesity promotes inflammation in periaortic adipose tissue and angiotensin II-induced abdominal aortic aneurysm formation. Arterioscler Thromb Vasc Biol. 2009;29(10):1458–64.

    Article  CAS  Google Scholar 

  8. Li C, Wang Z, Wang C, Ma Q, Zhao Y. Perivascular adipose tissue-derived adiponectin inhibits collar-induced carotid atherosclerosis by promoting macrophage autophagy. PLoS One. 2015;10(5):e0124031.

    Article  Google Scholar 

  9. Sakaue T, Suzuki J, Hamaguchi M, Suehiro C, Tanino A, Nagao T et al. Perivascular adipose tissue angiotensin II type 1 receptor promotes vascular inflammation and aneurysm formation. Hypertension. 2017;70(4):780–789.

    Article  CAS  Google Scholar 

  10. Fleenor BS, Eng JS, Sindler AL, Pham BT, Kloor JD, Seals DR. Superoxide signaling in perivascular adipose tissue promotes age-related artery stiffness. Aging Cell. 2014;13(3):576–8.

    Article  CAS  Google Scholar 

  11. Hollan I, Prayson R, Saatvedt K, Almdahl SM, Nossent HC, Mikkelsen K, et al. Inflammatory cell infiltrates in vessels with different susceptibility to atherosclerosis in rheumatic and non-rheumatic patients. Circ J. 2008;72(12):1986–92.

    Article  Google Scholar 

  12. Öhman M, Luo W, Wang H, Guo C, Abdallah W, Russo H, et al. Perivascular visceral adipose tissue induces atherosclerosis in apolipoprotein E deficient mice. Atherosclerosis. 2011;219(1):33–9.

    Article  Google Scholar 

  13. Xia N, Horke S, Habermeier A, Closs EI, Reifenberg G, Gericke A, et al. Uncoupling of endothelial nitric oxide synthase in perivascular adipose tissue of diet-induced obese mice. Arterioscler Thromb Vasc Biol. 2016;36(1):78–85.

    Article  CAS  Google Scholar 

  14. Xia N, Förstermann U, Li H. Effects of resveratrol on eNOS in the endothelium and the perivascular adipose tissue. Ann N Y Acad Sci. 2017;1403:132–41.

    Article  CAS  Google Scholar 

  15. Wang P, Xu T-Y, Guan Y-F, Su D-F, Fan G-R, Miao C-Y. Perivascular adipose tissue-derived visfatin is a vascular smooth muscle cell growth factor: role of nicotinamide mononucleotide. Cardiovasc Res. 2009;81(2):370–80.

    Article  CAS  Google Scholar 

  16. Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A, et al. Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J Clin Endocrinol Metab. 2003;88(11):5163–8.

    Article  CAS  Google Scholar 

  17. Chatterjee TK, Stoll LL, Denning GM, Harrelson A, Blomkalns AL, Idelman G, et al. Proinflammatory phenotype of perivascular adipocytes: influence of high-fat feeding. Circ Res. 2009;104(4):541–9.

    Article  CAS  Google Scholar 

  18. Matsuda M, Shimomura I, Sata M, Arita Y, Nishida M, Maeda N, et al. Role of adiponectin in preventing vascular stenosis: the missing link of adipo-vascular axis. J Biol Chem. 2002;277(40):37487–91.

    Article  CAS  Google Scholar 

  19. Tian Z, Miyata K, Tazume H, Sakaguchi H, Kadomatsu T, Horio E, et al. Perivascular adipose tissue-secreted angiopoietin-like protein 2 (Angptl2) accelerates neointimal hyperplasia after endovascular injury. J Mol Cell Cardiol. 2013;57:1–12.

    Article  CAS  Google Scholar 

  20. Manka D, Chatterjee TK, Stoll LL, Basford JE, Konaniah ES, Srinivasan R, et al. Transplanted perivascular adipose tissue accelerates injury-induced neointimal hyperplasia: role of monocyte chemoattractant protein-1. Arterioscler Thromb Vasc Biol. 2014;34(8):1723–30.

    Article  CAS  Google Scholar 

  21. Benson TW, Weintraub DS, Crowe M, Yiew NKH, Popoola O, Pillai A, et al. Deletion of the Duffy antigen receptor for chemokines (DARC) promotes insulin resistance and adipose tissue inflammation during high fat feeding. Mol Cell Endocrinol. 2018;473:79–88.

    Article  CAS  Google Scholar 

  22. Qiang S, Nakatsu Y, Seno Y, Fujishiro M, Sakoda H, Kushiyama A, et al. Treatment with the SGLT2 inhibitor luseogliflozin improves nonalcoholic steatohepatitis in a rodent model with diabetes mellitus. Diabetol Metab Syndr. 2015;7:104.

    Article  Google Scholar 

  23. Bruder-Nascimento T, Kennard S, Antonova G, Mintz JD, Bence KK, Belin de Chantemele EJ. Ptp1b deletion in pro-opiomelanocortin neurons increases energy expenditure and impairs endothelial function via TNF-alpha dependent mechanisms. Clin Sci (Lond). 2016;130(11):881–93.

    Article  CAS  Google Scholar 

  24. Lee MH, Chen SJ, Tsao CM, Wu CC. Perivascular adipose tissue inhibits endothelial function of rat aortas via caveolin-1. PLoS One. 2014;9(6):e99947.

    Article  Google Scholar 

  25. Payne GA, Bohlen HG, Dincer UD, Borbouse L, Tune JD. Periadventitial adipose tissue impairs coronary endothelial function via PKC-beta-dependent phosphorylation of nitric oxide synthase. Am J Physiol Heart Circ Physiol. 2009;297(1):H460–5.

    Article  CAS  Google Scholar 

  26. Ketonen J, Shi J, Martonen E, Mervaala E. Periadventitial adipose tissue promotes endothelial dysfunction via oxidative stress in diet-induced obese C57Bl/6 mice. Circ J. 2010;74(7):1479–87.

    Article  CAS  Google Scholar 

  27. Cheng KK, Lam KS, Wang Y, Huang Y, Carling D, Wu D, et al. Adiponectin-induced endothelial nitric oxide synthase activation and nitric oxide production are mediated by APPL1 in endothelial cells. Diabetes. 2007;56(5):1387–94.

    Article  Google Scholar 

  28. Brown NK, Zhou Z, Zhang J, Zeng R, Wu J, Eitzman DT, et al. Perivascular adipose tissue in vascular function and disease: a review of current research and animal models. Arterioscler Thromb Vasc Biol. 2014;34(8):1621–30.

    Article  CAS  Google Scholar 

  29. Chang L, Milton H, Eitzman DT, Chen YE. Paradoxical roles of perivascular adipose tissue in atherosclerosis and hypertension. Circ J. 2013;77(1):11–8.

    Article  Google Scholar 

  30. Chang L, Villacorta L, Li R, Hamblin M, Xu W, Dou C, et al. Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-gamma deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis. Circulation. 2012;126(9):1067–78.

    Article  CAS  Google Scholar 

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Funding

This study was funded by grants HL124097, HL126949, HL134354, and AR070029 from the National Institutes of Health (N.L.W).

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Authors and Affiliations

  1. Department of Medicine, Cardiology Division, Vascular Biology Center, Medical College of Georgia at Augusta University, 1460 Laney Walker Blvd, Augusta, GA, 30912, USA

    Tetsuo Horimatsu, Aaron S. Patel, Rosaria Prasad, Lauren E. Reid, Tyler W. Benson, Abdalrahman Zarzour, Mourad Ogbi, Thiago Bruder do Nascimento, Eric Belin de Chantemele, Ha Won Kim & Neal L. Weintraub

  2. Pediatrics and Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA

    Brian K. Stansfield

  3. Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA

    Xin-Yun Lu

Authors
  1. Tetsuo Horimatsu
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  2. Aaron S. Patel
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  3. Rosaria Prasad
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  4. Lauren E. Reid
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  5. Tyler W. Benson
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  6. Abdalrahman Zarzour
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  7. Mourad Ogbi
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  8. Thiago Bruder do Nascimento
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  9. Eric Belin de Chantemele
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  11. Xin-Yun Lu
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  12. Ha Won Kim
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  13. Neal L. Weintraub
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Corresponding author

Correspondence to Neal L. Weintraub.

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The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants.

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Horimatsu, T., Patel, A.S., Prasad, R. et al. Remote Effects of Transplanted Perivascular Adipose Tissue on Endothelial Function and Atherosclerosis. Cardiovasc Drugs Ther 32, 503–510 (2018). https://doi.org/10.1007/s10557-018-6821-y

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