Endothelial Dysfunction in Obesity

  • Atilla EnginEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 960)


Chronic inflammatory state in obesity causes dysregulation of the endocrine and paracrine actions of adipocyte-derived factors, which disrupt vascular homeostasis and contribute to endothelial vasodilator dysfunction and subsequent hypertension. While normal healthy perivascular adipose tissue (PVAT) ensures the dilation of blood vessels, obesity-associated PVAT leads to a change in profile of the released adipo-cytokines, resulting in a decreased vasorelaxing effect. Adipose tissue inflammation, nitric oxide (NO)-bioavailability, insulin resistance and oxidized low-density lipoprotein (oxLDL) are main participating factors in endothelial dysfunction of obesity. In this chapter, disruption of inter-endothelial junctions between endothelial cells, significant increase in the production of reactive oxygen species (ROS), inflammation mediators, which are originated from inflamed endothelial cells, the balance between NO synthesis and ROS, insulin signaling and NO production, and decrease in l-arginine/endogenous asymmetric dimethyl-l-arginine (ADMA) ratio are discussed in connection with endothelial dysfunction in obesity.


Obesity Asymmetric dimethyl-l-arginine (ADMA) Nitric oxide (NO) Reactive oxygen species (ROS) Cyclic guanosine monophosphate (cGMP) Tumor necrosis factor-alpha (TNF-alpha) Endothelin-1 (ET-1) Endothelial nitric oxide synthase (eNOS) Endothelial nitric oxide synthase (eNOS) uncoupling Peroxynitrite Super oxide dismutase (SOD) Plasminogen-activator inhibitor-1 (PAI-1) Endothelium Saturated fatty acids Vasodilatory-stimulated phosphoprotein (VASP) Protein kinase C (PKC) Intercellular adhesion molecule-1 (ICAM-1) Pyrin domain-containing 3 (NLRP3) inflammasome Vascular cell adhesion molecule-1 (VCAM-1) Low-density lipoproteins (LDL) Oxidized low-density lipoprotein (OxLDL) Vascular endothelial growth factor (VEGF) Nuclear factor kappa-B (NF-kappaB) Inducible nitric oxide synthase (iNOS) 


  1. Agouni, A., S. Tual-Chalot, M. Chalopin, L. Duluc, N. Mody, M.C. Martinez, R. Andriantsitohaina, and M. Delibegović. 2014. Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction. Biochemical Pharmacology 92: 607–617. doi: 10.1016/j.bcp.2014.10.008.PubMedCrossRefGoogle Scholar
  2. Alessi, M.C., F. Peiretti, P. Morange, M. Henry, G. Nalbone, and I. Juhan-Vague. 1997. Production of plasminogen activator inhibitor 1 by human adipose tissue: Possible link between visceral fat accumulation and vascular disease. Diabetes 46: 860–867.PubMedCrossRefGoogle Scholar
  3. Ali, M.I., P. Ketsawatsomkron, E.J. Belin de Chantemele, J.D. Mintz, K. Muta, C. Salet, S.M. Black, M.L. Tremblay, D.J. Fulton, M.B. Marrero, and D.W. Stepp. 2009. Deletion of protein tyrosine phosphatase 1b improves peripheral insulin resistance and vascular function in obese, leptin-resistant mice via reduced oxidant tone. Circulation Research 105: 1013–1022. doi: 10.1161/CIRCRESAHA.109.206318.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Almabrouk, T.A., M.A. Ewart, I.P. Salt, and S. Kennedy. 2014. Perivascular fat, AMP-activated protein kinase and vascular diseases. British Journal of Pharmacology 171: 595–617. doi: 10.1111/bph.12479.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Anderssohn, M., E. Schwedhelm, N. Lüneburg, R.S. Vasan, and R.H. Böger. 2010. Asymmetric dimethylarginine as a mediator of vascular dysfunction and a marker of cardiovascular disease and mortality: An intriguing interaction with diabetes mellitus. Diabetes & Vascular Disease Research 7: 105–118. doi: 10.1177/1479164110366053.CrossRefGoogle Scholar
  6. Ando, J., and K. Yamamoto. 2011. Effects of shear stress and stretch on endothelial function. Antioxidants & Redox Signaling 15: 1389–1403. doi: 10.1089/ars.2010.3361.CrossRefGoogle Scholar
  7. Andreozzi, F., G. Formoso, S. Prudente, M.L. Hribal, A. Pandolfi, E. Bellacchio, S. Di Silvestre, V. Trischitta, A. Consoli, and G. Sesti. 2008. TRIB3 R84 variant is associated with impaired insulin-mediated nitric oxide production in human endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology 28: 1355–1360. doi: 10.1161/ATVBAHA.108.162883.PubMedCrossRefGoogle Scholar
  8. Antoniades, C., C. Shirodaria, P. Leeson, A. Antonopoulos, N. Warrick, T. Van-Assche, C. Cunnington, D. Tousoulis, R. Pillai, C. Ratnatunga, C. Stefanadis, and K.M. Channon. 2009. Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: Implications for endothelial function in human atherosclerosis. European Heart Journal 30: 1142–1150. doi: 10.1093/eurheartj/ehp061.PubMedCrossRefGoogle Scholar
  9. Antunes, T.T., A. Gagnon, B. Chen, F. Pacini, T.J. Smith, and A. Sorisky. 2006. Interleukin-6 release from human abdominal adipose cells is regulated by thyroid-stimulating hormone: Effect of adipocyte differentiation and anatomic depot. American Journal of Physiology: Endocrinology and Metabolism 290: E1140–E1144. doi: 10.1152/ajpendo.00516.2005.PubMedGoogle Scholar
  10. Arner, P. 2005. Human fat cell lipolysis: Biochemistry, regulation and clinical role. Best Practice & Research: Clinical Endocrinology & Metabolism 19: 471–482. doi: 10.1016/j.beem.2005.07.004.CrossRefGoogle Scholar
  11. Aung, H.H., M.W. Lame, K. Gohil, C.-I. An, D.W. Wilson, and J.C. Rutledge. 2013. Induction of ATF3 gene network by triglyceride-rich lipoprotein lipolysis products increases vascular apoptosis and inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology 33: 2088–2096. doi: 10.1161/ATVBAHA.113.301375.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Badimón, L., G. Vilahur, and T. Padró. 2009. Lipoproteins, platelets and atherothrombosis. Revista Española de Cardiología 62: 1161–1178.PubMedCrossRefGoogle Scholar
  13. Badimon, L., R.F. Storey, and G. Vilahur. 2011. Update on lipids, inflammation and atherothrombosis. Thrombosis and Haemostasis 105(Suppl 1): S34–S42. doi: 10.1160/THS10-11-0717.PubMedCrossRefGoogle Scholar
  14. Balda, M.S., and K. Matter. 2009. Tight junctions and the regulation of gene expression. Biochimica et Biophysica Acta 1788: 761–767. doi: 10.1016/j.bbamem.2008.11.024.PubMedCrossRefGoogle Scholar
  15. Basta, G., G. Lazzerini, S. Del Turco, G.M. Ratto, A.M. Schmidt, and R. De Caterina. 2005. At least 2 distinct pathways generating reactive oxygen species mediate vascular cell adhesion molecule-1 induction by advanced glycation end products. Arteriosclerosis, Thrombosis, and Vascular Biology 25: 1401–1407. doi: 10.1161/01.ATV.0000167522.48370.5e.PubMedCrossRefGoogle Scholar
  16. Bazzoni, G., and E. Dejana. 2004. Endothelial cell-to-cell junctions: Molecular organization and role in vascular homeostasis. Physiological Reviews 84: 869–901. doi: 10.1152/physrev.00035.2003.PubMedCrossRefGoogle Scholar
  17. Beckman, J.S., and W.H. Koppenol. 1996. Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and ugly. The American Journal of Physiology 271: C1424–C1437.PubMedGoogle Scholar
  18. Belin de Chantemele, E.J., and D.W. Stepp. 2012. Influence of obesity and metabolic dysfunction on the endothelial control in the coronary circulation. Journal of Molecular and Cellular Cardiology 52: 840–847. doi: 10.1016/j.yjmcc.2011.08.018.PubMedCrossRefGoogle Scholar
  19. Bharath, L.P., T. Ruan, Y. Li, A. Ravindran, X. Wan, J.K. Nhan, M.L. Walker, L. Deeter, R. Goodrich, E. Johnson, D. Munday, R. Mueller, D. Kunz, D. Jones, V. Reese, S.A. Summers, P.V.A. Babu, W.L. Holland, Q.-J. Zhang, E.D. Abel, and J.D. Symons. 2015. Ceramide-initiated protein phosphatase 2A activation contributes to arterial dysfunction in vivo. Diabetes 64: 3914–3926. doi: 10.2337/db15-0244.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Bhatia, L.S., N.P. Curzen, P.C. Calder, and C.D. Byrne. 2012. Non-alcoholic fatty liver disease: A new and important cardiovascular risk factor? European Heart Journal 33: 1190–1200. doi: 10.1093/eurheartj/ehr453.PubMedCrossRefGoogle Scholar
  21. Bitar, M.S., S. Wahid, S. Mustafa, E. Al-Saleh, G.S. Dhaunsi, and F. Al-Mulla. 2005. Nitric oxide dynamics and endothelial dysfunction in type II model of genetic diabetes. European Journal of Pharmacology 511: 53–64. doi: 10.1016/j.ejphar.2005.01.014.PubMedCrossRefGoogle Scholar
  22. Blaise, S., H. Polena, and I. Vilgrain. 2015. Soluble vascular endothelial-cadherin and auto-antibodies to human vascular endothelial-cadherin in human diseases: Two new biomarkers of endothelial dysfunction. Vascular Medicine (London, England) 20: 557–565. doi: 10.1177/1358863X15591201.CrossRefGoogle Scholar
  23. Böger, R.H., S.M. Bode-Böger, A. Szuba, P.S. Tsao, J.R. Chan, O. Tangphao, T.F. Blaschke, and J.P. Cooke. 1998. Asymmetric dimethylarginine (ADMA): A novel risk factor for endothelial dysfunction: Its role in hypercholesterolemia. Circulation 98: 1842–1847.PubMedCrossRefGoogle Scholar
  24. Böger, R.H., S.M. Bode-Böger, P.S. Tsao, P.S. Lin, J.R. Chan, and J.P. Cooke. 2000a. An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes. Journal of the American College of Cardiology 36: 2287–2295.PubMedCrossRefGoogle Scholar
  25. Böger, R.H., K. Sydow, J. Borlak, T. Thum, H. Lenzen, B. Schubert, D. Tsikas, and S.M. Bode-Böger. 2000b. LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: Involvement of S-adenosylmethionine-dependent methyltransferases. Circulation Research 87: 99–105.PubMedCrossRefGoogle Scholar
  26. Boubekeur, S., N. Boute, P. Pagesy, V. Zilberfarb, N. Christeff, and T. Issad. 2011. A new highly efficient substrate-trapping mutant of protein tyrosine phosphatase 1B (PTP1B) reveals full autoactivation of the insulin receptor precursor. The Journal of Biological Chemistry 286: 19373–19380. doi: 10.1074/jbc.M111.222984.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Braccini, L., E. Ciraolo, C.C. Campa, A. Perino, D.L. Longo, G. Tibolla, M. Pregnolato, Y. Cao, B. Tassone, F. Damilano, M. Laffargue, E. Calautti, M. Falasca, G.D. Norata, J.M. Backer, and E. Hirsch. 2015. PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling. Nature Communications 6: 7400. doi: 10.1038/ncomms8400.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Braunersreuther, V., F. Mach, and S. Steffens. 2007. The specific role of chemokines in atherosclerosis. Thrombosis and Haemostasis 97: 714–721.PubMedGoogle Scholar
  29. Campia, U., M. Tesauro, and C. Cardillo. 2012. Human obesity and endothelium-dependent responsiveness. British Journal of Pharmacology 165: 561–573. doi: 10.1111/j.1476-5381.2011.01661.x.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Cassuto, J., H. Dou, I. Czikora, A. Szabo, V.S. Patel, V. Kamath, E. Belin de Chantemele, A. Feher, M.J. Romero, and Z. Bagi. 2014. Peroxynitrite disrupts endothelial caveolae leading to eNOS uncoupling and diminished flow-mediated dilation in coronary arterioles of diabetic patients. Diabetes 63: 1381–1393. doi: 10.2337/db13-0577.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Cave, A.C., A.C. Brewer, A. Narayanapanicker, R. Ray, D.J. Grieve, S. Walker, and A.M. Shah. 2006. NADPH oxidases in cardiovascular health and disease. Antioxidants & Redox Signaling 8: 691–728. doi: 10.1089/ars.2006.8.691.CrossRefGoogle Scholar
  32. Chatterjee, T.K., B.J. Aronow, W.S. Tong, D. Manka, Y. Tang, V.Y. Bogdanov, D. Unruh, A.L. Blomkalns, M.G. Piegore, D.S. Weintraub, S.M. Rudich, D.G. Kuhel, D.Y. Hui, and N.L. Weintraub. 2013. Human coronary artery perivascular adipocytes overexpress genes responsible for regulating vascular morphology, inflammation, and hemostasis. Physiological Genomics 45: 697–709. doi: 10.1152/physiolgenomics.00042.2013.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Chen, H., M. Montagnani, T. Funahashi, I. Shimomura, and M.J. Quon. 2003. Adiponectin stimulates production of nitric oxide in vascular endothelial cells. The Journal of Biological Chemistry 278: 45021–45026. doi: 10.1074/jbc.M307878200.PubMedCrossRefGoogle Scholar
  34. Chen, C.-A., T.-Y. Wang, S. Varadharaj, L.A. Reyes, C. Hemann, M.A.H. Talukder, Y.-R. Chen, L.J. Druhan, and J.L. Zweier. 2010. S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature 468: 1115–1118. doi: 10.1038/nature09599.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Chen, Y., A.L. Pitzer, X. Li, P.-L. Li, L. Wang, and Y. Zhang. 2015. Instigation of endothelial Nlrp3 inflammasome by adipokine visfatin promotes inter-endothelial junction disruption: Role of HMGB1. Journal of Cellular and Molecular Medicine 19: 2715–2727. doi: 10.1111/jcmm.12657.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Cheng, K.K.Y., M.A. Iglesias, K.S.L. Lam, Y. Wang, G. Sweeney, W. Zhu, P.M. Vanhoutte, E.W. Kraegen, and A. Xu. 2009. APPL1 potentiates insulin-mediated inhibition of hepatic glucose production and alleviates diabetes via Akt activation in mice. Cell Metabolism 9: 417–427. doi: 10.1016/j.cmet.2009.03.013.PubMedCrossRefGoogle Scholar
  37. Cheng, A.M., N. Rizzo-DeLeon, C.L. Wilson, W.J. Lee, S. Tateya, A.W. Clowes, M.W. Schwartz, and F. Kim. 2014. Vasodilator-stimulated phosphoprotein protects against vascular inflammation and insulin resistance. American Journal of Physiology: Endocrinology and Metabolism 307: E571–E579. doi: 10.1152/ajpendo.00303.2014.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Cho, H. 2013. Protein tyrosine phosphatase 1B (PTP1B) and obesity. Vitamins and Hormones 91: 405–424. doi: 10.1016/B978-0-12-407766-9.00017-1.PubMedCrossRefGoogle Scholar
  39. Chou, I.-P., Y.Y. Lin, S.-T. Ding, and C.-Y. Chen. 2014. Adiponectin receptor 1 enhances fatty acid metabolism and cell survival in palmitate-treated HepG2 cells through the PI3 K/AKT pathway. European Journal of Nutrition 53: 907–917. doi: 10.1007/s00394-013-0594-7.PubMedCrossRefGoogle Scholar
  40. Christiansen, T., B. Richelsen, and J.M. Bruun. 2005. Monocyte chemoattractant protein-1 is produced in isolated adipocytes, associated with adiposity and reduced after weight loss in morbid obese subjects. International Journal of Obesity 2005(29): 146–150. doi: 10.1038/sj.ijo.0802839.CrossRefGoogle Scholar
  41. Chudek, J., and A. Wiecek. 2006. Adipose tissue, inflammation and endothelial dysfunction. Pharmacological Reports 58(Suppl): 81–88.PubMedGoogle Scholar
  42. Cigolini, M., G. Targher, I.A. Bergamo Andreis, M. Tonoli, G. Agostino, and G. De Sandre. 1996. Visceral fat accumulation and its relation to plasma hemostatic factors in healthy men. Arteriosclerosis, Thrombosis, and Vascular Biology 16: 368–374.PubMedCrossRefGoogle Scholar
  43. Cinti, S. 2011. Between brown and white: Novel aspects of adipocyte differentiation. Annals of Medicine 43: 104–115. doi: 10.3109/07853890.2010.535557.PubMedCrossRefGoogle Scholar
  44. Claffey, K.P., W.O. Wilkison, and B.M. Spiegelman. 1992. Vascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways. Journal of Biological Chemistry 267: 16317–16322.PubMedGoogle Scholar
  45. Codoñer-Franch, P., S. Tavárez-Alonso, R. Murria-Estal, J. Megías-Vericat, M. Tortajada-Girbés, and E. Alonso-Iglesias. 2011a. Nitric oxide production is increased in severely obese children and related to markers of oxidative stress and inflammation. Atherosclerosis 215: 475–480. doi: 10.1016/j.atherosclerosis.2010.12.035.PubMedCrossRefGoogle Scholar
  46. Codoñer-Franch, P., V. Valls-Bellés, A. Arilla-Codoñer, and E. Alonso-Iglesias. 2011b. Oxidant mechanisms in childhood obesity: The link between inflammation and oxidative stress. Translational Research, The Journal of Laboratory and Clinical Medicine 158: 369–384. doi: 10.1016/j.trsl.2011.08.004.CrossRefGoogle Scholar
  47. Collins, T., M.A. Read, A.S. Neish, M.Z. Whitley, D. Thanos, and T. Maniatis. 1995. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. The FASEB Journal 9: 899–909.PubMedGoogle Scholar
  48. Collot-Teixeira, S., J. Martin, C. McDermott-Roe, R. Poston, and J.L. McGregor. 2007. CD36 and macrophages in atherosclerosis. Cardiovascular Research 75: 468–477. doi: 10.1016/j.cardiores.2007.03.010.PubMedCrossRefGoogle Scholar
  49. Compher, C., and K.O. Badellino. 2008. Obesity and inflammation: Lessons from bariatric surgery. Journal of Parenteral and Enteral Nutrition 32: 645–647. doi: 10.1177/0148607108326070.PubMedCrossRefGoogle Scholar
  50. Crabtree, M.J., and K.M. Channon. 2011. Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease. Nitric Oxide: Biology and Chemistry 25: 81–88. doi: 10.1016/j.niox.2011.04.004.CrossRefGoogle Scholar
  51. Creager, M.A., T.F. Lüscher, F. Cosentino, and J.A. Beckman. 2003. Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part I. Circulation 108: 1527–1532. doi: 10.1161/01.CIR.0000091257.27563.32.PubMedCrossRefGoogle Scholar
  52. Davda, R.K., K.T. Stepniakowski, G. Lu, M.E. Ullian, T.L. Goodfriend, and B.M. Egan. 1995. Oleic acid inhibits endothelial nitric oxide synthase by a protein kinase C-independent mechanism. Hypertension: (Dallas, Tex. 1979) 26: 764–770.CrossRefGoogle Scholar
  53. Davignon, J., and P. Ganz. 2004. Role of endothelial dysfunction in atherosclerosis. Circulation 109: III27–III32. doi: 10.1161/01.CIR.0000131515.03336.f8.PubMedCrossRefGoogle Scholar
  54. Dejana, E., F. Orsenigo, and M.G. Lampugnani. 2008. The role of adherens junctions and VE-cadherin in the control of vascular permeability. Journal of Cell Science 121: 2115–2122. doi: 10.1242/jcs.017897.PubMedCrossRefGoogle Scholar
  55. Del Turco, S., T. Navarra, A. Gastaldelli, and G. Basta. 2011. Protective role of adiponectin on endothelial dysfunction induced by AGEs: A clinical and experimental approach. Microvascular Research 82: 73–76. doi: 10.1016/j.mvr.2011.03.003.PubMedCrossRefGoogle Scholar
  56. Deng, G., Y. Long, Y.-R. Yu, and M.-R. Li. 2010. Adiponectin directly improves endothelial dysfunction in obese rats through the AMPK-eNOS Pathway. International Journal of Obesity 2005(34): 165–171. doi: 10.1038/ijo.2009.205.CrossRefGoogle Scholar
  57. Devaraj, S., D.Y. Xu, and I. Jialal. 2003. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: Implications for the metabolic syndrome and atherothrombosis. Circulation 107: 398–404.PubMedCrossRefGoogle Scholar
  58. Drager, L.F., J. Li, M.-K. Shin, C. Reinke, N.R. Aggarwal, J.C. Jun, S. Bevans-Fonti, C. Sztalryd, S.M. O’Byrne, O. Kroupa, G. Olivecrona, W.S. Blaner, and V.Y. Polotsky. 2012. Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea. European Heart Journal 33: 783–790. doi: 10.1093/eurheartj/ehr097.PubMedCrossRefGoogle Scholar
  59. Du, X., D. Edelstein, S. Obici, N. Higham, M.-H. Zou, and M. Brownlee. 2006. Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. The Journal of Clinical Investigation 116: 1071–1080. doi: 10.1172/JCI23354.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Eid, H.M.A., T. Lyberg, H. Arnesen, and I. Seljeflot. 2007. Insulin and adiponectin inhibit the TNFalpha-induced ADMA accumulation in human endothelial cells: The role of DDAH. Atherosclerosis 194: e1–e8. doi: 10.1016/j.atherosclerosis.2006.11.008.PubMedCrossRefGoogle Scholar
  61. Eiselein, L., D.W. Wilson, M.W. Lamé, and J.C. Rutledge. 2007. Lipolysis products from triglyceride-rich lipoproteins increase endothelial permeability, perturb zonula occludens-1 and F-actin, and induce apoptosis. American Journal of Physiology: Heart and Circulatory Physiology 292: H2745–H2753. doi: 10.1152/ajpheart.00686.2006.PubMedGoogle Scholar
  62. El Assar, M., J.C. Ruiz de Adana, J. Angulo, M.L. Pindado Martínez, A. Hernández Matías, and L. Rodríguez-Mañas. 2013. Preserved endothelial function in human obesity in the absence of insulin resistance. Journal of Translational Medicine 11: 263. doi: 10.1186/1479-5876-11-263.PubMedPubMedCentralCrossRefGoogle Scholar
  63. Elms, S., F. Chen, Y. Wang, J. Qian, B. Askari, Y. Yu, D. Pandey, J. Iddings, R.B. Caldwell, and D.J.R. Fulton. 2013. Insights into the arginine paradox: Evidence against the importance of subcellular location of arginase and eNOS. American Journal of Physiology: Heart and Circulatory Physiology 305: H651–H666. doi: 10.1152/ajpheart.00755.2012.PubMedPubMedCentralGoogle Scholar
  64. Emorine, L., N. Blin, and A.D. Strosberg. 1994. The human beta 3-adrenoceptor: The search for a physiological function. Trends in Pharmacological Sciences 15: 3–7.PubMedCrossRefGoogle Scholar
  65. Eriksson, A.K.S., V. van Harmelen, B.M. Stenson, G. Aström, K. Wåhlén, J. Laurencikiene, and M. Rydén. 2009. Endothelin-1 stimulates human adipocyte lipolysis through the ET A receptor. International Journal of Obesity 2005(33): 67–74. doi: 10.1038/ijo.2008.212.CrossRefGoogle Scholar
  66. Erl, W., P.C. Weber, and C. Weber. 1998. Monocytic cell adhesion to endothelial cells stimulated by oxidized low density lipoprotein is mediated by distinct endothelial ligands. Atherosclerosis 136: 297–303.PubMedCrossRefGoogle Scholar
  67. Fain, J.N. 2006. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitamins and Hormones 74: 443–477. doi: 10.1016/S0083-6729(06)74018-3.PubMedCrossRefGoogle Scholar
  68. Fain, J.N., S.W. Bahouth, and A.K. Madan. 2004. TNFalpha release by the nonfat cells of human adipose tissue. International Journal of Obesity and Related Metabolic Disorders 28: 616–622. doi: 10.1038/sj.ijo.0802594.PubMedCrossRefGoogle Scholar
  69. Federici, M., R. Menghini, A. Mauriello, M.L. Hribal, F. Ferrelli, D. Lauro, P. Sbraccia, L.G. Spagnoli, G. Sesti, and R. Lauro. 2002. Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells. Circulation 106: 466–472.PubMedCrossRefGoogle Scholar
  70. Fiorentino, T.V., A. Prioletta, P. Zuo, and F. Folli. 2013. Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Current Pharmaceutical Design 19: 5695–5703.PubMedCrossRefGoogle Scholar
  71. Flavahan, N.A. 1992. Atherosclerosis or lipoprotein-induced endothelial dysfunction. Potential mechanisms underlying reduction in EDRF/nitric oxide activity. Circulation 85: 1927–1938.PubMedCrossRefGoogle Scholar
  72. Förstermann, U., and W.C. Sessa. 2012. Nitric oxide synthases: Regulation and function. European Heart Journal 33: 829–837, 837a–837d. doi:10.1093/eurheartj/ehr304.Google Scholar
  73. Fried, S.K., D.A. Bunkin, and A.S. Greenberg. 1998. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: Depot difference and regulation by glucocorticoid. The Journal of Clinical Endocrinology and Metabolism 83: 847–850. doi: 10.1210/jcem.83.3.4660.PubMedGoogle Scholar
  74. Fujisaka, S., I. Usui, A. Bukhari, M. Ikutani, T. Oya, Y. Kanatani, K. Tsuneyama, Y. Nagai, K. Takatsu, M. Urakaze, M. Kobayashi, and K. Tobe. 2009. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 58: 2574–2582. doi: 10.2337/db08-1475.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Fülöp, N., R.B. Marchase, and J.C. Chatham. 2007. Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system. Cardiovascular Research 73: 288–297. doi: 10.1016/j.cardiores.2006.07.018.PubMedCrossRefGoogle Scholar
  76. Gálvez-Prieto, B., J. Bolbrinker, P. Stucchi, A.I. de Las Heras, B. Merino, S. Arribas, M. Ruiz-Gayo, M. Huber, M. Wehland, R. Kreutz, and M.S. Fernandez-Alfonso. 2008. Comparative expression analysis of the renin-angiotensin system components between white and brown perivascular adipose tissue. The Journal of Endocrinology 197: 55–64. doi: 10.1677/JOE-07-0284.PubMedCrossRefGoogle Scholar
  77. Gámez-Méndez, A.M., H. Vargas-Robles, M. Arellano-Mendoza, E. Cruz-Laguna, A. Rios, and B. Escalante. 2014. Early stage of obesity potentiates nitric oxide reduction during the development of renal failure. Journal of Nephrology 27: 281–287. doi: 10.1007/s40620-013-0029-9.PubMedCrossRefGoogle Scholar
  78. Gamez-Mendez, A.M., H. Vargas-Robles, A. Ríos, and B. Escalante. 2015. Oxidative stress-dependent coronary endothelial dysfunction in obese mice. PLoS One 10: e0138609. doi: 10.1371/journal.pone.0138609.PubMedPubMedCentralCrossRefGoogle Scholar
  79. Gao, Y.-J. 2007. Dual modulation of vascular function by perivascular adipose tissue and its potential correlation with adiposity/lipoatrophy-related vascular dysfunction. Current Pharmaceutical Design 13: 2185–2192.PubMedCrossRefGoogle Scholar
  80. Gao, Y.-J., C. Lu, L.-Y. Su, A.M. Sharma, and R.M.K.W. Lee. 2007. Modulation of vascular function by perivascular adipose tissue: The role of endothelium and hydrogen peroxide. British Journal of Pharmacology 151: 323–331. doi: 10.1038/sj.bjp.0707228.PubMedPubMedCentralCrossRefGoogle Scholar
  81. García-Prieto, C.F., M. Gil-Ortega, I. Aránguez, M. Ortiz-Besoain, B. Somoza, and M.S. Fernández-Alfonso. 2015. Vascular AMPK as an attractive target in the treatment of vascular complications of obesity. Vascular Pharmacology 67–69: 10–20. doi: 10.1016/j.vph.2015.02.017.PubMedCrossRefGoogle Scholar
  82. Geraldes, P., and G.L. King. 2010. Activation of protein kinase C isoforms and its impact on diabetic complications. Circulation Research 106: 1319–1331. doi: 10.1161/CIRCRESAHA.110.217117.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Giacco, F., and M. Brownlee. 2010. Oxidative stress and diabetic complications. Circulation Research 107: 1058–1070. doi: 10.1161/CIRCRESAHA.110.223545.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Gil-Ortega, M., P. Stucchi, R. Guzmán-Ruiz, V. Cano, S. Arribas, M.C. González, M. Ruiz-Gayo, M.S. Fernández-Alfonso, and B. Somoza. 2010. Adaptative nitric oxide overproduction in perivascular adipose tissue during early diet-induced obesity. Endocrinology 151: 3299–3306. doi: 10.1210/en.2009-1464.PubMedCrossRefGoogle Scholar
  85. Gil-Ortega, M., L. Condezo-Hoyos, C.F. García-Prieto, S.M. Arribas, M.C. González, I. Aranguez, M. Ruiz-Gayo, B. Somoza, and M.S. Fernández-Alfonso. 2014. Imbalance between pro and anti-oxidant mechanisms in perivascular adipose tissue aggravates long-term high-fat diet-derived endothelial dysfunction. PLoS One 9: e95312. doi: 10.1371/journal.pone.0095312.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Gómez-Hernández, A., L. Perdomo, N. de las Heras, N. Beneit, O. Escribano, Y.F. Otero, C. Guillén, S. Díaz-Castroverde, B. Gozalbo-López, V. Cachofeiro, V. Lahera, and M. Benito. 2014. Antagonistic effect of TNF-alpha and insulin on uncoupling protein 2 (UCP-2) expression and vascular damage. Cardiovascular Diabetology 13: 108. doi: 10.1186/s12933-014-0108-9.PubMedPubMedCentralGoogle Scholar
  87. González-Mariscal, L., A. Betanzos, P. Nava, and B.E. Jaramillo. 2003. Tight junction proteins. Progress in Biophysics and Molecular Biology 81: 1–44.PubMedCrossRefGoogle Scholar
  88. Goossens, G.H., A. Bizzarri, N. Venteclef, Y. Essers, J.P. Cleutjens, E. Konings, J.W.E. Jocken, M. Cajlakovic, V. Ribitsch, K. Clément, and E.E. Blaak. 2011. Increased adipose tissue oxygen tension in obese compared with lean men is accompanied by insulin resistance, impaired adipose tissue capillarization, and inflammation. Circulation 124: 67–76. doi: 10.1161/CIRCULATIONAHA.111.027813.PubMedCrossRefGoogle Scholar
  89. Goossens, G.H., E.E. Blaak, R. Theunissen, A.M. Duijvestijn, K. Clément, J.-W.C. Tervaert, and M.M. Thewissen. 2012. Expression of NLRP3 inflammasome and T cell population markers in adipose tissue are associated with insulin resistance and impaired glucose metabolism in humans. Molecular Immunology 50: 142–149. doi: 10.1016/j.molimm.2012.01.005.PubMedCrossRefGoogle Scholar
  90. Grant, R.W., and J.M. Stephens. 2015. Fat in flames: Influence of cytokines and pattern recognition receptors on adipocyte lipolysis. American Journal of Physiology: Endocrinology and Metabolism 309: E205–E213. doi: 10.1152/ajpendo.00053.2015.PubMedCrossRefGoogle Scholar
  91. Gu, L., Y. Okada, S.K. Clinton, C. Gerard, G.K. Sukhova, P. Libby, and B.J. Rollins. 1998. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Molecular Cell 2: 275–281.PubMedCrossRefGoogle Scholar
  92. Guo, L., S. Tian, Y. Chen, Y. Mao, S. Cui, A. Hu, J. Zhang, S.-L. Xia, Y. Su, J. Du, E.R. Block, X.L. Wang, and Z. Cui. 2015. CAT-1 as a novel CAM stabilizes endothelial integrity and mediates the protective actions of L-Arg via a NO-independent mechanism. Journal of Molecular and Cellular Cardiology 87: 180–191. doi: 10.1016/j.yjmcc.2015.08.011.PubMedCrossRefGoogle Scholar
  93. Guzik, T.J., S. Mussa, D. Gastaldi, J. Sadowski, C. Ratnatunga, R. Pillai, and K.M. Channon. 2002. Mechanisms of increased vascular superoxide production in human diabetes mellitus: Role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 105: 1656–1662.PubMedCrossRefGoogle Scholar
  94. Guzik, T.J., D. Mangalat, and R. Korbut. 2006. Adipocytokines—Novel link between inflammation and vascular function? Journal of Physiology and Pharmacology 57: 505–528.PubMedGoogle Scholar
  95. Guzik, T.J., P.J. Marvar, M. Czesnikiewicz-Guzik, and R. Korbut. 2007. Perivascular adipose tissue as a messenger of the brain-vessel axis: Role in vascular inflammation and dysfunction. Journal of Physiology and Pharmacology 58: 591–610.PubMedGoogle Scholar
  96. Han, K.H., R.K. Tangirala, S.R. Green, and O. Quehenberger. 1998. Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes. A regulatory role for plasma LDL. Arteriosclerosis Thrombosis and Vascular Biology 18: 1983–1991.CrossRefGoogle Scholar
  97. Handa, P., S. Tateya, N.O. Rizzo, A.M. Cheng, V. Morgan-Stevenson, C.-Y. Han, A.W. Clowes, G. Daum, K.D. O’Brien, M.W. Schwartz, A. Chait, and F. Kim. 2011. Reduced vascular nitric oxide-cGMP signaling contributes to adipose tissue inflammation during high-fat feeding. Arteriosclerosis, Thrombosis, and Vascular Biology 31: 2827–2835. doi: 10.1161/ATVBAHA.111.236554.PubMedPubMedCentralCrossRefGoogle Scholar
  98. Haruna, Y., Y. Morita, N. Komai, T. Yada, T. Sakuta, N. Tomita, D.A. Fox, and N. Kashihara. 2006. Endothelial dysfunction in rat adjuvant-induced arthritis: Vascular superoxide production by NAD(P)H oxidase and uncoupled endothelial nitric oxide synthase. Arthritis and Rheumatism 54: 1847–1855. doi: 10.1002/art.21891.PubMedCrossRefGoogle Scholar
  99. Hatanaka, M., S. Shimba, M. Sakaue, Y. Kondo, H. Kagechika, K. Kokame, T. Miyata, and S. Hara. 2009. Hypoxia-inducible factor-3alpha functions as an accelerator of 3T3-L1 adipose differentiation. Biological & Pharmaceutical Bulletin 32: 1166–1172.CrossRefGoogle Scholar
  100. He, Q., Z. Gao, J. Yin, J. Zhang, Z. Yun, and J. Ye. 2011. Regulation of HIF-1{alpha} activity in adipose tissue by obesity-associated factors: Adipogenesis, insulin, and hypoxia. American Journal of Physiology: Endocrinology and Metabolism 300: E877–E885. doi: 10.1152/ajpendo.00626.2010.PubMedPubMedCentralGoogle Scholar
  101. Heilbronn, L.K., and L.V. Campbell. 2008. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Current Pharmaceutical Design 14: 1225–1230.PubMedCrossRefGoogle Scholar
  102. Hernandez, S., B. Chavez Munguia, and L. Gonzalez-Mariscal. 2007. ZO-2 silencing in epithelial cells perturbs the gate and fence function of tight junctions and leads to an atypical monolayer architecture. Experimental Cell Research 313: 1533–1547. doi: 10.1016/j.yexcr.2007.01.026.PubMedCrossRefGoogle Scholar
  103. Hirabara, S.M., R. Curi, and P. Maechler. 2010. Saturated fatty acid-induced insulin resistance is associated with mitochondrial dysfunction in skeletal muscle cells. Journal of Cellular Physiology 222: 187–194. doi: 10.1002/jcp.21936.PubMedCrossRefGoogle Scholar
  104. Holvoet, P., D. De Keyzer, and D.R. Jacobs. 2008a. Oxidized LDL and the metabolic syndrome. Future Lipidology 3: 637–649. doi: 10.2217/17460875.3.6.637.PubMedPubMedCentralCrossRefGoogle Scholar
  105. Holvoet, P., D.-H. Lee, M. Steffes, M. Gross, and D.R. Jacobs. 2008b. Association between circulating oxidized low-density lipoprotein and incidence of the metabolic syndrome. JAMA 299: 2287–2293. doi: 10.1001/jama.299.19.2287.PubMedPubMedCentralCrossRefGoogle Scholar
  106. Hosogai, N., A. Fukuhara, K. Oshima, Y. Miyata, S. Tanaka, K. Segawa, S. Furukawa, Y. Tochino, R. Komuro, M. Matsuda, and I. Shimomura. 2007. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56: 901–911. doi: 10.2337/db06-0911.PubMedCrossRefGoogle Scholar
  107. Hotamisligil, G.S., P. Peraldi, A. Budavari, R. Ellis, M.F. White, and B.M. Spiegelman. 1996. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271: 665–668.PubMedCrossRefGoogle Scholar
  108. Huh, J.Y., Y.J. Park, M. Ham, and J.B. Kim. 2014. Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. Molecular Cells 37: 365–371. doi: 10.14348/molcells.2014.0074.CrossRefGoogle Scholar
  109. Hulsmans, M., B. Geeraert, T. Arnould, C. Tsatsanis, and P. Holvoet. 2013. PPAR agonist-induced reduction of Mcp1 in atherosclerotic plaques of obese, insulin-resistant mice depends on adiponectin-induced Irak3 expression. PLoS One 8: e62253. doi: 10.1371/journal.pone.0062253.PubMedPubMedCentralCrossRefGoogle Scholar
  110. Inoguchi, T., P. Li, F. Umeda, H.Y. Yu, M. Kakimoto, M. Imamura, T. Aoki, T. Etoh, T. Hashimoto, M. Naruse, H. Sano, H. Utsumi, and H. Nawata. 2000. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49: 1939–1945.PubMedCrossRefGoogle Scholar
  111. Ito, A., P.S. Tsao, S. Adimoolam, M. Kimoto, T. Ogawa, and J.P. Cooke. 1999. Novel mechanism for endothelial dysfunction: Dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 99: 3092–3095.PubMedCrossRefGoogle Scholar
  112. Jacobs, M., M.M.J. van Greevenbroek, C.J.H. van der Kallen, I. Ferreira, E.E. Blaak, E.J.M. Feskens, E.H.J.M. Jansen, C.G. Schalkwijk, and C.D.A. Stehouwer. 2009. Low-grade inflammation can partly explain the association between the metabolic syndrome and either coronary artery disease or severity of peripheral arterial disease: The CODAM study. European Journal of Clinical Investigation 39: 437–444. doi: 10.1111/j.1365-2362.2009.02129.x.PubMedCrossRefGoogle Scholar
  113. Jaishy, B., Q. Zhang, H.S. Chung, C. Riehle, J. Soto, S. Jenkins, P. Abel, L.A. Cowart, J.E. Van Eyk, and E.D. Abel. 2015. Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity. Journal of Lipid Research 56: 546–561. doi: 10.1194/jlr.M055152.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Jiang, Z.Y., Y.W. Lin, A. Clemont, E.P. Feener, K.D. Hein, M. Igarashi, T. Yamauchi, M.F. White, and G.L. King. 1999. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. The Journal of Clinical Investigation 104: 447–457. doi: 10.1172/JCI5971.PubMedPubMedCentralCrossRefGoogle Scholar
  115. Jurado-Pueyo, M., P.M. Campos, F. Mayor, and C. Murga. 2008. GRK2-dependent desensitization downstream of G proteins. Journal of Receptor and Signal Transduction Research 28: 59–70. doi: 10.1080/10799890801941939.PubMedCrossRefGoogle Scholar
  116. Keane, K.N., V.F. Cruzat, R. Carlessi, P.I.H. de Bittencourt, and P. Newsholme. 2015. Molecular events linking oxidative stress and inflammation to insulin resistance and β-cell dysfunction. Oxidative Medicine and Cellular Longevity 2015: 181643. doi: 10.1155/2015/181643.PubMedPubMedCentralCrossRefGoogle Scholar
  117. Kern, P.A., S. Ranganathan, C. Li, L. Wood, and G. Ranganathan. 2001. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. American Journal of Physiology: Endocrinology and Metabolism 280: E745–E751.PubMedGoogle Scholar
  118. Ketonen, J., J. Shi, E. Martonen, and E. Mervaala. 2010. Periadventitial adipose tissue promotes endothelial dysfunction via oxidative stress in diet-induced obese C57Bl/6 mice. Circulation Journal 74: 1479–1487.PubMedCrossRefGoogle Scholar
  119. Kietadisorn, R., R.P. Juni, and A.L. Moens. 2012. Tackling endothelial dysfunction by modulating NOS uncoupling: New insights into its pathogenesis and therapeutic possibilities. American Journal of Physiology: Endocrinology and Metabolism 302: E481–E495. doi: 10.1152/ajpendo.00540.2011.PubMedGoogle Scholar
  120. Kim, J., M. Montagnani, K.K. Koh, and M.J. Quon. 2006a. Reciprocal relationships between insulin resistance and endothelial dysfunction: Molecular and pathophysiological mechanisms. Circulation 113: 1888–1904. doi: 10.1161/CIRCULATIONAHA.105.563213.PubMedCrossRefGoogle Scholar
  121. Kim, C.-S., H.-S. Park, T. Kawada, J.-H. Kim, D. Lim, N.E. Hubbard, B.-S. Kwon, K.L. Erickson, and R. Yu. 2006b. Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. International Journal of Obesity 2005(30): 1347–1355. doi: 10.1038/sj.ijo.0803259.CrossRefGoogle Scholar
  122. Kim, F., M. Pham, I. Luttrell, D.D. Bannerman, J. Tupper, J. Thaler, T.R. Hawn, E.W. Raines, and M.W. Schwartz. 2007. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circulation Research 100: 1589–1596. doi: 10.1161/CIRCRESAHA.106.142851.PubMedCrossRefGoogle Scholar
  123. Kim, F., M. Pham, E. Maloney, N.O. Rizzo, G.J. Morton, B.E. Wisse, E.A. Kirk, A. Chait, and M.W. Schwartz. 2008. Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance. Arteriosclerosis, Thrombosis, and Vascular Biology 28: 1982–1988. doi: 10.1161/ATVBAHA.108.169722.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Kim, S.-H., J.-W. Lee, J.-A. Im, and H.-J. Hwang. 2011. Monocyte chemoattractant protein-1 is related to metabolic syndrome and homocysteine in subjects without clinically significant atherosclerotic cardiovascular disease. Scandinavian Journal of Clinical and Laboratory Investigation 71: 1–6. doi: 10.3109/00365513.2010.519047.PubMedCrossRefGoogle Scholar
  125. Kleinert, H., A. Pautz, K. Linker, and P.M. Schwarz. 2004. Regulation of the expression of inducible nitric oxide synthase. European Journal of Pharmacology 500: 255–266. doi: 10.1016/j.ejphar.2004.07.030.PubMedCrossRefGoogle Scholar
  126. Kobayashi, T., K. Taguchi, T. Yasuhiro, T. Matsumoto, and K. Kamata. 2004. Impairment of PI3-K/Akt pathway underlies attenuated endothelial function in aorta of type 2 diabetic mouse model. Hypertension: (Dallas, Tex. 1979) 44: 956–962. doi: 10.1161/01.HYP.0000147559.10261.a7.CrossRefGoogle Scholar
  127. Koh, E.H., M. Kim, K.C. Ranjan, H.S. Kim, H.-S. Park, K.S. Oh, I.-S. Park, W.J. Lee, M.-S. Kim, J.-Y. Park, J.H. Youn, and K.-U. Lee. 2010. eNOS plays a major role in adiponectin synthesis in adipocytes. American Journal of Physiology: Endocrinology and Metabolism 298: E846–E853. doi: 10.1152/ajpendo.00008.2010.PubMedGoogle Scholar
  128. Kohler, H.-P. 2002. Insulin resistance syndrome: Interaction with coagulation and fibrinolysis. Swiss Medical Weekly 132: 241–252.PubMedGoogle Scholar
  129. Kone, B.C., T. Kuncewicz, W. Zhang, and Z.-Y. Yu. 2003. Protein interactions with nitric oxide synthases: Controlling the right time, the right place, and the right amount of nitric oxide. American Journal of Physiology: Renal Physiology 285: F178–F190. doi: 10.1152/ajprenal.00048.2003.PubMedGoogle Scholar
  130. Koren, S., and I.G. Fantus. 2007. Inhibition of the protein tyrosine phosphatase PTP1B: Potential therapy for obesity, insulin resistance and type-2 diabetes mellitus. Best Practice & Research: Clinical Endocrinology & Metabolism 21: 621–640. doi: 10.1016/j.beem.2007.08.004.CrossRefGoogle Scholar
  131. Kovacova, Z., M. Tencerova, B. Roussel, Z. Wedellova, L. Rossmeislova, D. Langin, J. Polak, and V. Stich. 2012. The impact of obesity on secretion of adiponectin multimeric isoforms differs in visceral and subcutaneous adipose tissue. International Journal of Obesity 2005(36): 1360–1365. doi: 10.1038/ijo.2011.223.CrossRefGoogle Scholar
  132. Kuboki, K., Z.Y. Jiang, N. Takahara, S.W. Ha, M. Igarashi, T. Yamauchi, E.P. Feener, T.P. Herbert, C.J. Rhodes, and G.L. King. 2000. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: A specific vascular action of insulin. Circulation 101: 676–681.PubMedCrossRefGoogle Scholar
  133. Lastra, G., and C. Manrique. 2015. Perivascular adipose tissue, inflammation and insulin resistance: Link to vascular dysfunction and cardiovascular disease. Hormone Molecular Biology and Clinical Investigation 22: 19–26. doi: 10.1515/hmbci-2015-0010.PubMedCrossRefGoogle Scholar
  134. Lee, Y., S.-H. Lee, E.S. Jung, J.-S. Kim, C.Y. Shim, Y.-G. Ko, D. Choi, Y. Jang, N. Chung, and J.-W. Ha. 2010. Visceral adiposity and the severity of coronary artery disease in middle-aged subjects with normal waist circumference and its relation with lipocalin-2 and MCP-1. Atherosclerosis 213: 592–597. doi: 10.1016/j.atherosclerosis.2010.09.012.PubMedCrossRefGoogle Scholar
  135. Li, H., and U. Förstermann. 2013. Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease. Current Opinion in Pharmacology 13: 161–167. doi: 10.1016/j.coph.2013.01.006.PubMedCrossRefGoogle Scholar
  136. Li, R., W.-Q. Wang, H. Zhang, X. Yang, Q. Fan, T.A. Christopher, B.L. Lopez, L. Tao, B.J. Goldstein, F. Gao, and X.L. Ma. 2007. Adiponectin improves endothelial function in hyperlipidemic rats by reducing oxidative/nitrative stress and differential regulation of eNOS/iNOS activity. American Journal of Physiology: Endocrinology and Metabolism 293: E1703–E1708. doi: 10.1152/ajpendo.00462.2007.PubMedGoogle Scholar
  137. Liang, C.-F., J.T. Liu, Y. Wang, A. Xu, and P.M. Vanhoutte. 2013. Toll-like receptor 4 mutation protects obese mice against endothelial dysfunction by decreasing NADPH oxidase isoforms 1 and 4. Arteriosclerosis, Thrombosis, and Vascular Biology 33: 777–784. doi: 10.1161/ATVBAHA.112.301087.PubMedCrossRefGoogle Scholar
  138. Liangpunsakul, S., and N. Chalasani. 2005. Unexplained elevations in alanine aminotransferase in individuals with the metabolic syndrome: Results from the third National Health and Nutrition Survey (NHANES III). The American Journal of the Medical Sciences 329: 111–116.PubMedCrossRefGoogle Scholar
  139. Liao, J.K., W.S. Shin, W.Y. Lee, and S.L. Clark. 1995. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. The Journal of Biological Chemistry 270: 319–324.PubMedCrossRefGoogle Scholar
  140. Libby, P. 2002. Inflammation in atherosclerosis. Nature 420: 868–874. doi: 10.1038/nature01323.PubMedCrossRefGoogle Scholar
  141. Libby, P., P.M. Ridker, and A. Maseri. 2002. Inflammation and atherosclerosis. Circulation 105: 1135–1143.PubMedCrossRefGoogle Scholar
  142. Lim, S., and J.B. Meigs. 2014. Links between ectopic fat and vascular disease in humans. Arteriosclerosis, Thrombosis, and Vascular Biology 34: 1820–1826. doi: 10.1161/ATVBAHA.114.303035.PubMedPubMedCentralCrossRefGoogle Scholar
  143. Lin, K.Y., A. Ito, T. Asagami, P.S. Tsao, S. Adimoolam, M. Kimoto, H. Tsuji, G.M. Reaven, and J.P. Cooke. 2002. Impaired nitric oxide synthase pathway in diabetes mellitus: Role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 106: 987–992.PubMedCrossRefGoogle Scholar
  144. Lin, L.-Y., C.-Y. Lin, T.-C. Su, and C.-S. Liau. 2004. Angiotensin II-induced apoptosis in human endothelial cells is inhibited by adiponectin through restoration of the association between endothelial nitric oxide synthase and heat shock protein 90. FEBS Letters 574: 106–110. doi: 10.1016/j.febslet.2004.08.012.PubMedCrossRefGoogle Scholar
  145. Lin, L.-Y., W.-J. Lee, H.-N. Shen, W.-S. Yang, N.-H. Pai, T.-C. Su, and C.-S. Liau. 2007. Nitric oxide production is paradoxically decreased after weight reduction surgery in morbid obesity patients. Atherosclerosis 190: 436–442. doi: 10.1016/j.atherosclerosis.2006.02.033.PubMedCrossRefGoogle Scholar
  146. Loria, P., A. Lonardo, L. Carulli, A.M. Verrone, M. Ricchi, S. Lombardini, A. Rudilosso, S. Ballestri, and N. Carulli. 2005. Review article: The metabolic syndrome and non-alcoholic fatty liver disease. Alimentary Pharmacology & Therapeutics 22(Suppl 2): 31–36. doi: 10.1111/j.1365-2036.2005.02592.x.CrossRefGoogle Scholar
  147. Lu, C., L.-Y. Su, R.M.K.W. Lee, and Y.-J. Gao. 2010. Mechanisms for perivascular adipose tissue-mediated potentiation of vascular contraction to perivascular neuronal stimulation: The role of adipocyte-derived angiotensin II. European Journal of Pharmacology 634: 107–112. doi: 10.1016/j.ejphar.2010.02.006.PubMedCrossRefGoogle Scholar
  148. Lu, C., A.X. Zhao, Y.-J. Gao, and R.M.K.W. Lee. 2011. Modulation of vein function by perivascular adipose tissue. European Journal of Pharmacology 657: 111–116. doi: 10.1016/j.ejphar.2010.12.028.PubMedCrossRefGoogle Scholar
  149. Luan, B., J. Zhao, H. Wu, B. Duan, G. Shu, X. Wang, D. Li, W. Jia, J. Kang, and G. Pei. 2009. Deficiency of a beta-arrestin-2 signal complex contributes to insulin resistance. Nature 457: 1146–1149. doi: 10.1038/nature07617.PubMedCrossRefGoogle Scholar
  150. Luo, Y., X. Ma, X. Pan, Y. Xu, Q. Xiong, Y. Xiao, Y. Bao, and W. Jia. 2016. Serum lipocalin-2 levels are positively associated with not only total body fat but also visceral fat area in Chinese men. Medicine (Baltimore) 95: e4039. doi: 10.1097/MD.0000000000004039.CrossRefGoogle Scholar
  151. Lyon, C.J., R.E. Law, and W.A. Hsueh. 2003. Minireview: Adiposity, inflammation, and atherogenesis. Endocrinology 144: 2195–2200. doi: 10.1210/en.2003-0285.PubMedCrossRefGoogle Scholar
  152. Ma, L., S. Ma, H. He, D. Yang, X. Chen, Z. Luo, D. Liu, and Z. Zhu. 2010. Perivascular fat-mediated vascular dysfunction and remodeling through the AMPK/mTOR pathway in high-fat diet-induced obese rats. Hypertension Research 33: 446–453. doi: 10.1038/hr.2010.11.PubMedCrossRefGoogle Scholar
  153. Madonna, R., A. Pandolfi, M. Massaro, A. Consoli, and R. De Caterina. 2004. Insulin enhances vascular cell adhesion molecule-1 expression in human cultured endothelial cells through a pro-atherogenic pathway mediated by p38 mitogen-activated protein-kinase. Diabetologia 47: 532–536. doi: 10.1007/s00125-004-1330-x.PubMedCrossRefGoogle Scholar
  154. Marliss, E.B., S. Chevalier, R. Gougeon, J.A. Morais, M. Lamarche, O.A. Adegoke, and G. Wu. 2006. Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover. Diabetologia 49: 351–359. doi: 10.1007/s00125-005-0066-6.PubMedCrossRefGoogle Scholar
  155. Masella, R., R. Varì, M. D’Archivio, C. Santangelo, B. Scazzocchio, M.T. Maggiorella, L. Sernicola, F. Titti, M. Sanchez, U. Di Mario, G. Leto, and C. Giovannini. 2006. Oxidised LDL modulate adipogenesis in 3T3-L1 preadipocytes by affecting the balance between cell proliferation and differentiation. FEBS Letters 580: 2421–2429. doi: 10.1016/j.febslet.2006.03.068.PubMedCrossRefGoogle Scholar
  156. McGavock, J.M., R.G. Victor, R.H. Unger, L.S. Szczepaniak, and American College of Physicians and the American Physiological Society. 2006. Adiposity of the heart, revisited. Annals of Internal Medicine 144: 517–524.PubMedCrossRefGoogle Scholar
  157. Mehra, V.C., E. Jackson, X.M. Zhang, X.-C. Jiang, L.W. Dobrucki, J. Yu, P. Bernatchez, A.J. Sinusas, G.I. Shulman, W.C. Sessa, T.O. Yarovinsky, and J.R. Bender. 2014. Ceramide-activated phosphatase mediates fatty acid-induced endothelial VEGF resistance and impaired angiogenesis. The American Journal of Pathology 184: 1562–1576. doi: 10.1016/j.ajpath.2014.01.009.PubMedPubMedCentralCrossRefGoogle Scholar
  158. Mehta, J.L., J. Chen, P.L. Hermonat, F. Romeo, and G. Novelli. 2006. Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): A critical player in the development of atherosclerosis and related disorders. Cardiovascular Research 69: 36–45. doi: 10.1016/j.cardiores.2005.09.006.PubMedCrossRefGoogle Scholar
  159. Meijer, K., M. de Vries, S. Al-Lahham, M. Bruinenberg, D. Weening, M. Dijkstra, N. Kloosterhuis, R.J. van der Leij, H. van der Want, B.-J. Kroesen, R. Vonk, and F. Rezaee. 2011. Human primary adipocytes exhibit immune cell function: Adipocytes prime inflammation independent of macrophages. PLoS One 6: e17154. doi: 10.1371/journal.pone.0017154.PubMedPubMedCentralCrossRefGoogle Scholar
  160. Michel, T., and O. Feron. 1997. Nitric oxide synthases: Which, where, how, and why? The Journal of Clinical Investigation 100: 2146–2152. doi: 10.1172/JCI119750.PubMedPubMedCentralCrossRefGoogle Scholar
  161. Millar, T.M., C.R. Stevens, N. Benjamin, R. Eisenthal, R. Harrison, and D.R. Blake. 1998. Xanthine oxidoreductase catalyses the reduction of nitrates and nitrite to nitric oxide under hypoxic conditions. FEBS Letters 427: 225–228.PubMedCrossRefGoogle Scholar
  162. Montagnani, M., I. Golovchenko, I. Kim, G.Y. Koh, M.L. Goalstone, A.N. Mundhekar, M. Johansen, D.F. Kucik, M.J. Quon, and B. Draznin. 2002a. Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. The Journal of Biological Chemistry 277: 1794–1799. doi: 10.1074/jbc.M103728200.PubMedCrossRefGoogle Scholar
  163. Montagnani, M., L.V. Ravichandran, H. Chen, D.L. Esposito, and M.J. Quon. 2002b. Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells. Molecular Endocrinology (Baltimore, Md.) 16: 1931–1942. doi: 10.1210/me.2002-0074.CrossRefGoogle Scholar
  164. Mornex, J.F., Y. Martinet, K. Yamauchi, P.B. Bitterman, G.R. Grotendorst, A. Chytil-Weir, G.R. Martin, and R.G. Crystal. 1986. Spontaneous expression of the c-sis gene and release of a platelet-derived growth factorlike molecule by human alveolar macrophages. The Journal of Clinical Investigation 78: 61–66. doi: 10.1172/JCI112574.PubMedPubMedCentralCrossRefGoogle Scholar
  165. Mukherjee, T.K., S. Mukhopadhyay, and J.R. Hoidal. 2005. The role of reactive oxygen species in TNFalpha-dependent expression of the receptor for advanced glycation end products in human umbilical vein endothelial cells. Biochimica et Biophysica Acta 1744: 213–223. doi: 10.1016/j.bbamcr.2005.03.007.PubMedCrossRefGoogle Scholar
  166. Mundy, A.L., E. Haas, I. Bhattacharya, C.C. Widmer, M. Kretz, K. Baumann, and M. Barton. 2007. Endothelin stimulates vascular hydroxyl radical formation: Effect of obesity. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 293: R2218–R2224. doi: 10.1152/ajpregu.00295.2007.PubMedCrossRefGoogle Scholar
  167. Mustafa, S., V. Sharma, and J.H. McNeill. 2009. Insulin resistance and endothelial dysfunction: Are epoxyeicosatrienoic acids the link? Experimental and Clinical Cardiology 14: e41–e50.PubMedPubMedCentralGoogle Scholar
  168. Navab, M., S.S. Imes, S.Y. Hama, G.P. Hough, L.A. Ross, R.W. Bork, A.J. Valente, J.A. Berliner, D.C. Drinkwater, and H. Laks. 1991. Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. The Journal of Clinical Investigation 88: 2039–2046. doi: 10.1172/JCI115532.PubMedPubMedCentralCrossRefGoogle Scholar
  169. Nishimura, S., I. Manabe, M. Nagasaki, K. Seo, H. Yamashita, Y. Hosoya, M. Ohsugi, K. Tobe, T. Kadowaki, R. Nagai, and S. Sugiura. 2008. In vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue. The Journal of Clinical Investigation 118: 710–721. doi: 10.1172/JCI33328.PubMedPubMedCentralGoogle Scholar
  170. Norata, G.D., L. Grigore, S. Raselli, L. Redaelli, A. Hamsten, F. Maggi, P. Eriksson, and A.L. Catapano. 2007. Post-prandial endothelial dysfunction in hypertriglyceridemic subjects: Molecular mechanisms and gene expression studies. Atherosclerosis 193: 321–327. doi: 10.1016/j.atherosclerosis.2006.09.015.PubMedCrossRefGoogle Scholar
  171. Noronha, B.T., J.-M. Li, S.B. Wheatcroft, A.M. Shah, and M.T. Kearney. 2005. Inducible nitric oxide synthase has divergent effects on vascular and metabolic function in obesity. Diabetes 54: 1082–1089.PubMedCrossRefGoogle Scholar
  172. Nyqvist, D., C. Giampietro, and E. Dejana. 2008. Deciphering the functional role of endothelial junctions by using in vivo models. EMBO Reports 9: 742–747. doi: 10.1038/embor.2008.123.PubMedPubMedCentralCrossRefGoogle Scholar
  173. Omar, A., T.K. Chatterjee, Y. Tang, D.Y. Hui, and N.L. Weintraub. 2014. Proinflammatory phenotype of perivascular adipocytes. Arteriosclerosis, Thrombosis, and Vascular Biology 34: 1631–1636. doi: 10.1161/ATVBAHA.114.303030.PubMedPubMedCentralCrossRefGoogle Scholar
  174. Oriowo, M.A. 2015. Perivascular adipose tissue, vascular reactivity and hypertension. Medical Principles and Practice 24(Suppl 1): 29–37. doi: 10.1159/000356380.PubMedCrossRefGoogle Scholar
  175. Owen, C., A. Czopek, A. Agouni, L. Grant, R. Judson, E.K. Lees, G.D. Mcilroy, O. Göransson, A. Welch, K.K. Bence, B.B. Kahn, B.G. Neel, N. Mody, and M. Delibegović. 2012. Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis. PLoS One 7: e32700. doi: 10.1371/journal.pone.0032700.PubMedPubMedCentralCrossRefGoogle Scholar
  176. Ozen, G., A. Daci, X. Norel, and G. Topal. 2015. Human perivascular adipose tissue dysfunction as a cause of vascular disease: Focus on vascular tone and wall remodeling. European Journal of Pharmacology 766: 16–24. doi: 10.1016/j.ejphar.2015.09.012.PubMedCrossRefGoogle Scholar
  177. Packard, R.R.S., A.H. Lichtman, and P. Libby. 2009. Innate and adaptive immunity in atherosclerosis. Seminars in Immunopathology 31: 5–22. doi: 10.1007/s00281-009-0153-8.PubMedPubMedCentralCrossRefGoogle Scholar
  178. Paneni, F., J.A. Beckman, M.A. Creager, and F. Cosentino. 2013. Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part I. European Heart Journal 34: 2436–2443. doi: 10.1093/eurheartj/eht149.PubMedPubMedCentralCrossRefGoogle Scholar
  179. Pang, C., Z. Gao, J. Yin, J. Zhang, W. Jia, and J. Ye. 2008. Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity. American Journal of Physiology: Endocrinology and Metabolism 295: E313–E322. doi: 10.1152/ajpendo.90296.2008.PubMedPubMedCentralCrossRefGoogle Scholar
  180. Panzhinskiy, E., J. Ren, and S. Nair. 2013. Protein tyrosine phosphatase 1B and insulin resistance: Role of endoplasmic reticulum stress/reactive oxygen species/nuclear factor kappa B axis. PLoS One 8: e77228. doi: 10.1371/journal.pone.0077228.PubMedPubMedCentralCrossRefGoogle Scholar
  181. Park, S.Y., J. Ryu, and W. Lee. 2005. O-GlcNAc modification on IRS-1 and Akt2 by PUGNAc inhibits their phosphorylation and induces insulin resistance in rat primary adipocytes. Experimental & Molecular Medicine 37: 220–229. doi: 10.1038/emm.2005.30.CrossRefGoogle Scholar
  182. Park, M., A. Sabetski, Y. Kwan Chan, S. Turdi, and G. Sweeney. 2015. Palmitate induces ER stress and autophagy in H9c2 cells: Implications for apoptosis and adiponectin resistance. Journal of Cellular Physiology 230: 630–639. doi: 10.1002/jcp.24781.PubMedCrossRefGoogle Scholar
  183. Perkins, J.M., N.G. Joy, D.B. Tate, and S.N. Davis. 2015. Acute effects of hyperinsulinemia and hyperglycemia on vascular inflammatory biomarkers and endothelial function in overweight and obese humans. American Journal of Physiology: Endocrinology and Metabolism 309: E168–E176. doi: 10.1152/ajpendo.00064.2015.PubMedPubMedCentralGoogle Scholar
  184. Perticone, F., R. Ceravolo, M. Candigliota, G. Ventura, S. Iacopino, F. Sinopoli, and P.L. Mattioli. 2001. Obesity and body fat distribution induce endothelial dysfunction by oxidative stress: Protective effect of vitamin C. Diabetes 50: 159–165.PubMedCrossRefGoogle Scholar
  185. Picchi, A., X. Gao, S. Belmadani, B.J. Potter, M. Focardi, W.M. Chilian, and C. Zhang. 2006. Tumor necrosis factor-alpha induces endothelial dysfunction in the prediabetic metabolic syndrome. Circulation Research 99: 69–77. doi: 10.1161/01.RES.0000229685.37402.80.PubMedCrossRefGoogle Scholar
  186. Pierce, G.L., L.A. Lesniewski, B.R. Lawson, S.D. Beske, and D.R. Seals. 2009. Nuclear factor-{kappa}B activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans. Circulation 119: 1284–1292. doi: 10.1161/CIRCULATIONAHA.108.804294.PubMedPubMedCentralCrossRefGoogle Scholar
  187. Prieur, X., C.Y.L. Mok, V.R. Velagapudi, V. Núñez, L. Fuentes, D. Montaner, K. Ishikawa, A. Camacho, N. Barbarroja, S. O’Rahilly, J.K. Sethi, J. Dopazo, M. Orešič, M. Ricote, and A. Vidal-Puig. 2011. Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes 60: 797–809. doi: 10.2337/db10-0705.PubMedPubMedCentralCrossRefGoogle Scholar
  188. Qiao, L., B. Kinney, J. Schaack, and J. Shao. 2011. Adiponectin inhibits lipolysis in mouse adipocytes. Diabetes 60: 1519–1527. doi: 10.2337/db10-1017.PubMedPubMedCentralCrossRefGoogle Scholar
  189. Rajavashisth, T.B., A. Andalibi, M.C. Territo, J.A. Berliner, M. Navab, A.M. Fogelman, and A.J. Lusis. 1990. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature 344: 254–257. doi: 10.1038/344254a0.PubMedCrossRefGoogle Scholar
  190. Rajsheker, S., D. Manka, A.L. Blomkalns, T.K. Chatterjee, L.L. Stoll, and N.L. Weintraub. 2010. Crosstalk between perivascular adipose tissue and blood vessels. Current Opinion in Pharmacology 10: 191–196. doi: 10.1016/j.coph.2009.11.005.PubMedPubMedCentralCrossRefGoogle Scholar
  191. Rask-Madsen, C., and G.L. King. 2005. Proatherosclerotic mechanisms involving protein kinase C in diabetes and insulin resistance. Arteriosclerosis, Thrombosis, and Vascular Biology 25: 487–496. doi: 10.1161/01.ATV.0000155325.41507.e0.PubMedCrossRefGoogle Scholar
  192. Read, M.A., M.Z. Whitley, A.J. Williams, and T. Collins. 1994. NF-kappa B and I kappa B alpha: An inducible regulatory system in endothelial activation. The Journal of Experimental Medicine 179: 503–512.PubMedCrossRefGoogle Scholar
  193. Reiter, E., and R.J. Lefkowitz. 2006. GRKs and beta-arrestins: Roles in receptor silencing, trafficking and signaling. Trends in Endocrinology and Metabolism 17: 159–165. doi: 10.1016/j.tem.2006.03.008.PubMedCrossRefGoogle Scholar
  194. Rizzo, N.O., E. Maloney, M. Pham, I. Luttrell, H. Wessells, S. Tateya, G. Daum, P. Handa, M.W. Schwartz, and F. Kim. 2010. Reduced NO-cGMP signaling contributes to vascular inflammation and insulin resistance induced by high-fat feeding. Arteriosclerosis, Thrombosis, and Vascular Biology 30: 758–765. doi: 10.1161/ATVBAHA.109.199893.PubMedPubMedCentralCrossRefGoogle Scholar
  195. Roberts-Toler, C., B.T. O’Neill, and A.M. Cypess. 2015. Diet-induced obesity causes insulin resistance in mouse brown adipose tissue. Obesity (Silver Spring, Md.) 23: 1765–1770. doi: 10.1002/oby.21134.CrossRefGoogle Scholar
  196. Rojas, E., D. Rodríguez-Molina, P. Bolli, Z.H. Israili, J. Faría, E. Fidilio, V. Bermúdez, and M. Velasco. 2014. The role of adiponectin in endothelial dysfunction and hypertension. Current Hypertension Reports 16: 463. doi: 10.1007/s11906-014-0463-7.PubMedCrossRefGoogle Scholar
  197. Sansbury, B.E., T.D. Cummins, Y. Tang, J. Hellmann, C.R. Holden, M.A. Harbeson, Y. Chen, R.P. Patel, M. Spite, A. Bhatnagar, and B.G. Hill. 2012. Overexpression of endothelial nitric oxide synthase prevents diet-induced obesity and regulates adipocyte phenotype. Circulation Research 111: 1176–1189. doi: 10.1161/CIRCRESAHA.112.266395.PubMedPubMedCentralCrossRefGoogle Scholar
  198. Sawamura, T., N. Kume, T. Aoyama, H. Moriwaki, H. Hoshikawa, Y. Aiba, T. Tanaka, S. Miwa, Y. Katsura, T. Kita, and T. Masaki. 1997. An endothelial receptor for oxidized low-density lipoprotein. Nature 386: 73–77. doi: 10.1038/386073a0.PubMedCrossRefGoogle Scholar
  199. Schrammel, A., M. Mussbacher, G. Wölkart, H. Stessel, K. Pail, S. Winkler, M. Schweiger, G. Haemmerle, W. Al Zoughbi, G. Höfler, A. Lametschwandtner, R. Zechner, and B. Mayer. 2014. Endothelial dysfunction in adipose triglyceride lipase deficiency. Biochimica et Biophysica Acta 1841: 906–917. doi: 10.1016/j.bbalip.2014.03.005.PubMedPubMedCentralCrossRefGoogle Scholar
  200. Schwartz, E.A., and P.D. Reaven. 2012. Lipolysis of triglyceride-rich lipoproteins, vascular inflammation, and atherosclerosis. Biochimica et Biophysica Acta 1821: 858–866. doi: 10.1016/j.bbalip.2011.09.021.PubMedCrossRefGoogle Scholar
  201. Shah, A., N. Mehta, and M.P. Reilly. 2008. Adipose inflammation, insulin resistance, and cardiovascular disease. Journal of Parenteral and Enteral Nutrition 32: 638–644. doi: 10.1177/0148607108325251.PubMedPubMedCentralCrossRefGoogle Scholar
  202. Shaw, P.X. 2004. Rethinking oxidized low-density lipoprotein, its role in atherogenesis and the immune responses associated with it. Archivum Immunologiae et Therapiae Experimentalis (Warsz) 52: 225–239.Google Scholar
  203. Shepherd, P.R., D.J. Withers, and K. Siddle. 1998. Phosphoinositide 3-kinase: The key switch mechanism in insulin signalling. The Biochemical Journal 333(Pt 3): 471–490.PubMedPubMedCentralCrossRefGoogle Scholar
  204. Shin, S., S. Mohan, and H.-L. Fung. 2011. Intracellular L-arginine concentration does not determine NO production in endothelial cells: Implications on the “L-arginine paradox.”. Biochemical and Biophysical Research Communications 414: 660–663. doi: 10.1016/j.bbrc.2011.09.112.PubMedPubMedCentralCrossRefGoogle Scholar
  205. Shoelson, S.E., L. Herrero, and A. Naaz. 2007. Obesity, inflammation, and insulin resistance. Gastroenterology 132: 2169–2180. doi: 10.1053/j.gastro.2007.03.059.PubMedCrossRefGoogle Scholar
  206. Silver, A.E., S.D. Beske, D.D. Christou, A.J. Donato, K.L. Moreau, I. Eskurza, P.E. Gates, and D.R. Seals. 2007. Overweight and obese humans demonstrate increased vascular endothelial NAD(P)H oxidase-p47(phox) expression and evidence of endothelial oxidative stress. Circulation 115: 627–637. doi: 10.1161/CIRCULATIONAHA.106.657486.PubMedCrossRefGoogle Scholar
  207. Simionescu, M. 2007. Implications of early structural-functional changes in the endothelium for vascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology 27: 266–274. doi: 10.1161/01.ATV.0000253884.13901.e4.PubMedCrossRefGoogle Scholar
  208. Sowa, G., M. Pypaert, and W.C. Sessa. 2001. Distinction between signaling mechanisms in lipid rafts vs. caveolae. Proceedings of the National Academy of Sciences of the United States of America 98: 14072–14077. doi: 10.1073/pnas.241409998.PubMedPubMedCentralCrossRefGoogle Scholar
  209. Spiroglou, S.G., C.G. Kostopoulos, J.N. Varakis, and H.H. Papadaki. 2010. Adipokines in periaortic and epicardial adipose tissue: Differential expression and relation to atherosclerosis. Journal of Atherosclerosis and Thrombosis 17: 115–130.PubMedCrossRefGoogle Scholar
  210. Steinberg, H.O., H. Chaker, R. Leaming, A. Johnson, G. Brechtel, and A.D. Baron. 1996. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. The Journal of Clinical Investigation 97: 2601–2610. doi: 10.1172/JCI118709.PubMedPubMedCentralCrossRefGoogle Scholar
  211. Steinberg, H.O., M. Tarshoby, R. Monestel, G. Hook, J. Cronin, A. Johnson, B. Bayazeed, and A.D. Baron. 1997. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. The Journal of Clinical Investigation 100: 1230–1239. doi: 10.1172/JCI119636.PubMedPubMedCentralCrossRefGoogle Scholar
  212. Stühlinger, M.C., F. Abbasi, J.W. Chu, C. Lamendola, T.L. McLaughlin, J.P. Cooke, G.M. Reaven, and P.S. Tsao. 2002. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 287: 1420–1426.PubMedCrossRefGoogle Scholar
  213. Sun, X., N. Hou, F. Han, Y. Guo, Z. Hui, G. Du, and Y. Zhang. 2013. Effect of high free fatty acids on the anti-contractile response of perivascular adipose tissue in rat aorta. Journal of Molecular and Cellular Cardiology 63: 169–174. doi: 10.1016/j.yjmcc.2013.07.018.PubMedCrossRefGoogle Scholar
  214. Symons, J.D., and E.D. Abel. 2013. Lipotoxicity contributes to endothelial dysfunction: A focus on the contribution from ceramide. Reviews in Endocrine & Metabolic Disorders 14: 59–68. doi: 10.1007/s11154-012-9235-3.CrossRefGoogle Scholar
  215. Symons, J.D., S.L. McMillin, C. Riehle, J. Tanner, M. Palionyte, E. Hillas, D. Jones, R.C. Cooksey, M.J. Birnbaum, D.A. McClain, Q.-J. Zhang, D. Gale, L.J. Wilson, and E.D. Abel. 2009. Contribution of insulin and Akt1 signaling to endothelial nitric oxide synthase in the regulation of endothelial function and blood pressure. Circulation Research 104: 1085–1094. doi: 10.1161/CIRCRESAHA.108.189316.PubMedPubMedCentralCrossRefGoogle Scholar
  216. Szasz, T., and R.C. Webb. 2012. Perivascular adipose tissue: More than just structural support. Clinical Science (London, England: 1979) 122: 1–12. doi: 10.1042/CS20110151.CrossRefGoogle Scholar
  217. Taguchi, K., T. Kobayashi, T. Matsumoto, and K. Kamata. 2011. Dysfunction of endothelium-dependent relaxation to insulin via PKC-mediated GRK2/Akt activation in aortas of ob/ob mice. American Journal of Physiology: Heart and Circulatory Physiology 301: H571–H583. doi: 10.1152/ajpheart.01189.2010.PubMedGoogle Scholar
  218. Taguchi, K., T. Matsumoto, K. Kamata, and T. Kobayashi. 2012. G protein-coupled receptor kinase 2, with β-arrestin 2, impairs insulin-induced Akt/endothelial nitric oxide synthase signaling in ob/ob mouse aorta. Diabetes 61: 1978–1985. doi: 10.2337/db11-1729.PubMedPubMedCentralCrossRefGoogle Scholar
  219. Taguchi, K., T. Matsumoto, and T. Kobayashi. 2015. G-protein-coupled receptor kinase 2 and endothelial dysfunction: Molecular insights and pathophysiological mechanisms. Journal of Smooth Muscle Research 51: 37–49. doi: 10.1540/jsmr.51.37.PubMedPubMedCentralCrossRefGoogle Scholar
  220. Thal, D.M., R.Y. Yeow, C. Schoenau, J. Huber, and J.J.G. Tesmer. 2011. Molecular mechanism of selectivity among G protein-coupled receptor kinase 2 inhibitors. Molecular Pharmacology 80: 294–303. doi: 10.1124/mol.111.071522.PubMedPubMedCentralCrossRefGoogle Scholar
  221. Thalmann, S., and C.A. Meier. 2007. Local adipose tissue depots as cardiovascular risk factors. Cardiovascular Research 75: 690–701. doi: 10.1016/j.cardiores.2007.03.008.PubMedCrossRefGoogle Scholar
  222. Topal, G., J.-L.G. Topal, A. Brunet, L. Walch, J.-L. Boucher, and M. David-Dufilho. 2006. Mitochondrial arginase II modulates nitric-oxide synthesis through nonfreely exchangeable L-arginine pools in human endothelial cells. The Journal of Pharmacology and Experimental Therapeutics 318: 1368–1374. doi: 10.1124/jpet.106.103747.PubMedCrossRefGoogle Scholar
  223. Trochu, J.N., V. Leblais, Y. Rautureau, F. Bévérelli, H. Le Marec, A. Berdeaux, and C. Gauthier. 1999. Beta 3-adrenoceptor stimulation induces vasorelaxation mediated essentially by endothelium-derived nitric oxide in rat thoracic aorta. British Journal of Pharmacology 128: 69–76. doi: 10.1038/sj.bjp.0702797.PubMedPubMedCentralCrossRefGoogle Scholar
  224. Tschopp, J., and K. Schroder. 2010. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nature Reviews: Immunology 10: 210–215. doi: 10.1038/nri2725.PubMedGoogle Scholar
  225. Uittenbogaard, A., P.W. Shaul, I.S. Yuhanna, A. Blair, and E.J. Smart. 2000. High density lipoprotein prevents oxidized low density lipoprotein-induced inhibition of endothelial nitric-oxide synthase localization and activation in caveolae. The Journal of Biological Chemistry 275: 11278–11283.PubMedCrossRefGoogle Scholar
  226. van Harmelen, V., A. Eriksson, G. Aström, K. Wåhlén, E. Näslund, F. Karpe, K. Frayn, T. Olsson, J. Andersson, M. Rydén, and P. Arner. 2008. Vascular peptide endothelin-1 links fat accumulation with alterations of visceral adipocyte lipolysis. Diabetes 57: 378–386. doi: 10.2337/db07-0893.PubMedCrossRefGoogle Scholar
  227. van Tits, L., J. de Graaf, H. Toenhake, W. van Heerde, and A. Stalenhoef. 2005. C-reactive protein and annexin A5 bind to distinct sites of negatively charged phospholipids present in oxidized low-density lipoprotein. Arteriosclerosis, Thrombosis, and Vascular Biology 25: 717–722. doi: 10.1161/01.ATV.0000157979.51673.2c.PubMedCrossRefGoogle Scholar
  228. Vandanmagsar, B., Y.-H. Youm, A. Ravussin, J.E. Galgani, K. Stadler, R.L. Mynatt, E. Ravussin, J.M. Stephens, and V.D. Dixit. 2011. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature Medicine 17: 179–188. doi: 10.1038/nm.2279.PubMedPubMedCentralCrossRefGoogle Scholar
  229. Vandenbroucke, E., D. Mehta, R. Minshall, and A.B. Malik. 2008. Regulation of endothelial junctional permeability. Annals of the New York Academy of Sciences 1123: 134–145. doi: 10.1196/annals.1420.016.PubMedCrossRefGoogle Scholar
  230. Vanhaesebroeck, B., S.J. Leevers, K. Ahmadi, J. Timms, R. Katso, P.C. Driscoll, R. Woscholski, P.J. Parker, and M.D. Waterfield. 2001. Synthesis and function of 3-phosphorylated inositol lipids. Annual Review of Biochemistry 70: 535–602. doi: 10.1146/annurev.biochem.70.1.535.PubMedCrossRefGoogle Scholar
  231. Venugopal, S.K., S. Devaraj, I. Yuhanna, P. Shaul, and I. Jialal. 2002. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation 106: 1439–1441.PubMedCrossRefGoogle Scholar
  232. Vidal, F., C. Colomé, J. Martínez-González, and L. Badimon. 1998. Atherogenic concentrations of native low-density lipoproteins down-regulate nitric-oxide-synthase mRNA and protein levels in endothelial cells. European Journal of Biochemistry 252: 378–384.PubMedCrossRefGoogle Scholar
  233. Virdis, A., F. Santini, R. Colucci, E. Duranti, G. Salvetti, I. Rugani, C. Segnani, M. Anselmino, N. Bernardini, C. Blandizzi, A. Salvetti, A. Pinchera, and S. Taddei. 2011. Vascular generation of tumor necrosis factor-α reduces nitric oxide availability in small arteries from visceral fat of obese patients. Journal of the American College of Cardiology 58: 238–247. doi: 10.1016/j.jacc.2011.01.050.PubMedCrossRefGoogle Scholar
  234. Virdis, A., E. Duranti, C. Rossi, U. Dell’Agnello, E. Santini, M. Anselmino, M. Chiarugi, S. Taddei, and A. Solini. 2015. Tumour necrosis factor-alpha participates on the endothelin-1/nitric oxide imbalance in small arteries from obese patients: Role of perivascular adipose tissue. European Heart Journal 36: 784–794. doi: 10.1093/eurheartj/ehu072.PubMedCrossRefGoogle Scholar
  235. Virkamäki, A., K. Ueki, and C.R. Kahn. 1999. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. The Journal of Clinical Investigation 103: 931–943. doi: 10.1172/JCI6609.PubMedPubMedCentralCrossRefGoogle Scholar
  236. Wakana, N., D. Irie, M. Kikai, K. Terada, K. Yamamoto, H. Kawahito, T. Kato, T. Ogata, T. Ueyama, S. Matoba, and H. Yamada. 2015. Maternal high-fat diet exaggerates atherosclerosis in adult offspring by augmenting periaortic adipose tissue-specific proinflammatory response. Arteriosclerosis, Thrombosis, and Vascular Biology 35: 558–569. doi: 10.1161/ATVBAHA.114.305122.PubMedCrossRefGoogle Scholar
  237. Waki, H., and P. Tontonoz. 2007. Endocrine functions of adipose tissue. Annual Review of Pathology 2: 31–56. doi: 10.1146/annurev.pathol.2.010506.091859.PubMedCrossRefGoogle Scholar
  238. Walston, J., R.E. Andersen, M. Seibert, H. Hilfiker, B. Beamer, J. Blumenthal, and E.T. Poehlman. 2003. Arg64 beta3-adrenoceptor variant and the components of energy expenditure. Obesity Research 11: 509–511. doi: 10.1038/oby.2003.71.PubMedCrossRefGoogle Scholar
  239. Wang, L., A.R. Sapuri-Butti, H.H. Aung, A.N. Parikh, and J.C. Rutledge. 2008. Triglyceride-rich lipoprotein lipolysis increases aggregation of endothelial cell membrane microdomains and produces reactive oxygen species. American Journal of Physiology: Heart and Circulatory Physiology 295: H237–H244. doi: 10.1152/ajpheart.01366.2007.PubMedPubMedCentralCrossRefGoogle Scholar
  240. Wang, L., R. Gill, T.L. Pedersen, L.J. Higgins, J.W. Newman, and J.C. Rutledge. 2009a. Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation. Journal of Lipid Research 50: 204–213. doi: 10.1194/jlr.M700505-JLR200.PubMedPubMedCentralCrossRefGoogle Scholar
  241. Wang, P., T.-Y. Xu, Y.-F. Guan, D.-F. Su, G.-R. Fan, and C.-Y. Miao. 2009b. Perivascular adipose tissue-derived visfatin is a vascular smooth muscle cell growth factor: Role of nicotinamide mononucleotide. Cardiovascular Research 81: 370–380. doi: 10.1093/cvr/cvn288.PubMedCrossRefGoogle Scholar
  242. Wang, Y.I., J. Schulze, N. Raymond, T. Tomita, K. Tam, S.I. Simon, and A.G. Passerini. 2011. Endothelial inflammation correlates with subject triglycerides and waist size after a high-fat meal. American Journal of Physiology: Heart and Circulatory Physiology 300: H784–H791. doi: 10.1152/ajpheart.01036.2010.PubMedGoogle Scholar
  243. Weber, C., L. Fraemohs, and E. Dejana. 2007. The role of junctional adhesion molecules in vascular inflammation. Nature Reviews: Immunology 7: 467–477. doi: 10.1038/nri2096.PubMedGoogle Scholar
  244. Wei, Y., G. Liu, J. Yang, R. Zheng, L. Jiang, and P. Bao. 2013. The association between metabolic syndrome and vascular endothelial dysfunction in adolescents. Experimental and Therapeutic Medicine 5: 1663–1666. doi: 10.3892/etm.2013.1055.PubMedPubMedCentralGoogle Scholar
  245. Weil, B.R., C.M. Westby, G.P. Van Guilder, J.J. Greiner, B.L. Stauffer, and C.A. DeSouza. 2011. Enhanced endothelin-1 system activity with overweight and obesity. American Journal of Physiology: Heart and Circulatory Physiology 301: H689–H695. doi: 10.1152/ajpheart.00206.2011.PubMedPubMedCentralGoogle Scholar
  246. Weisberg, S.P., D. McCann, M. Desai, M. Rosenbaum, R.L. Leibel, and A.W. Ferrante. 2003. Obesity is associated with macrophage accumulation in adipose tissue. The Journal of Clinical Investigation 112: 1796–1808. doi: 10.1172/JCI19246.PubMedPubMedCentralCrossRefGoogle Scholar
  247. Wen, H., D. Gris, Y. Lei, S. Jha, L. Zhang, M.T.-H. Huang, W.J. Brickey, and J.P.-Y. Ting. 2011. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nature Immunology 12: 408–415. doi: 10.1038/ni.2022.PubMedPubMedCentralCrossRefGoogle Scholar
  248. Williams, I.L., S.B. Wheatcroft, A.M. Shah, and M.T. Kearney. 2002. Obesity, atherosclerosis and the vascular endothelium: Mechanisms of reduced nitric oxide bioavailability in obese humans. International Journal of Obesity and Related Metabolic Disorders 26: 754–764. doi: 10.1038/sj.ijo.0801995.PubMedCrossRefGoogle Scholar
  249. Xia, M., K.M. Boini, J.M. Abais, M. Xu, Y. Zhang, and P.-L. Li. 2014. Endothelial NLRP3 inflammasome activation and enhanced neointima formation in mice by adipokine visfatin. The American Journal of Pathology 184: 1617–1628. doi: 10.1016/j.ajpath.2014.01.032.PubMedPubMedCentralCrossRefGoogle Scholar
  250. Xiao, X., Y. Dong, J. Zhong, R. Cao, X. Zhao, G. Wen, and J. Liu. 2011. Adiponectin protects endothelial cells from the damages induced by the intermittent high level of glucose. Endocrine 40: 386–393. doi: 10.1007/s12020-011-9531-9.PubMedCrossRefGoogle Scholar
  251. Xu, H., A.V. Hertzel, K.A. Steen, Q. Wang, J. Suttles, and D.A. Bernlohr. 2015. Uncoupling lipid metabolism from inflammation through fatty acid binding protein-dependent expression of UCP2. Molecular and Cellular Biology 35: 1055–1065. doi: 10.1128/MCB.01122-14.PubMedPubMedCentralCrossRefGoogle Scholar
  252. Yang, Z., and X.-F. Ming. 2013. Arginase: The emerging therapeutic target for vascular oxidative stress and inflammation. Frontiers in Immunology 4: 149. doi: 10.3389/fimmu.2013.00149.PubMedPubMedCentralCrossRefGoogle Scholar
  253. Ye, J. 2011. Adipose tissue vascularization: Its role in chronic inflammation. Current Diabetes Reports 11: 203–210. doi: 10.1007/s11892-011-0183-1.PubMedPubMedCentralCrossRefGoogle Scholar
  254. Ye, J., Z. Gao, J. Yin, and Q. He. 2007. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. American Journal of Physiology: Endocrinology and Metabolism 293: E1118–E1128. doi: 10.1152/ajpendo.00435.2007.PubMedGoogle Scholar
  255. Yu, Y., A.G. Rajapakse, J.-P. Montani, Z. Yang, and X.-F. Ming. 2014. p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-uncoupling in obesity. Cardiovascular Diabetology 13: 113. doi: 10.1186/s12933-014-0113-z.PubMedPubMedCentralCrossRefGoogle Scholar
  256. Yudkin, J.S., C.D. Stehouwer, J.J. Emeis, and S.W. Coppack. 1999. C-reactive protein in healthy subjects: Associations with obesity, insulin resistance, and endothelial dysfunction: A potential role for cytokines originating from adipose tissue? Arteriosclerosis, Thrombosis, and Vascular Biology 19: 972–978.PubMedCrossRefGoogle Scholar
  257. Zeng, G., F.H. Nystrom, L.V. Ravichandran, L.N. Cong, M. Kirby, H. Mostowski, and M.J. Quon. 2000. Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 101: 1539–1545.PubMedCrossRefGoogle Scholar
  258. Zhang, Q.-J., W.L. Holland, L. Wilson, J.M. Tanner, D. Kearns, J.M. Cahoon, D. Pettey, J. Losee, B. Duncan, D. Gale, C.A. Kowalski, N. Deeter, A. Nichols, M. Deesing, C. Arrant, T. Ruan, C. Boehme, D.R. McCamey, J. Rou, K. Ambal, K.K. Narra, S.A. Summers, E.D. Abel, and J.D. Symons. 2012. Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex. Diabetes 61: 1848–1859. doi: 10.2337/db11-1399.PubMedPubMedCentralCrossRefGoogle Scholar
  259. Zhang, Y., X. Li, A.L. Pitzer, Y. Chen, L. Wang, and P.-L. Li. 2015. Coronary endothelial dysfunction induced by nucleotide oligomerization domain-like receptor protein with pyrin domain containing 3 inflammasome activation during hypercholesterolemia: Beyond inflammation. Antioxidants & Redox Signaling 22: 1084–1096. doi: 10.1089/ars.2014.5978.CrossRefGoogle Scholar
  260. Zhao, L., Z. Fu, J. Wu, K.W. Aylor, E.J. Barrett, W. Cao, and Z. Liu. 2015. Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity. Clinical Science (London, England: 1979) 129: 1025–1036. doi: 10.1042/CS20150143.CrossRefGoogle Scholar
  261. Zhu, L., L. Hu, X. Li, G. Wang, W. Shan, L. Ma, and X. Wang. 2010. Relationship between Trp64Arg mutation in the β3-adrenergic receptor gene and metabolic syndrome: A seven-year follow-up study. Chinese Medical Journal 123: 2375–2378.PubMedGoogle Scholar
  262. Ziccardi, P., F. Nappo, G. Giugliano, K. Esposito, R. Marfella, M. Cioffi, F. D’Andrea, A.M. Molinari, and D. Giugliano. 2002. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 105: 804–809.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Faculty of Medicine, Department of General SurgeryGazi UniversityBesevlerTurkey
  2. 2.CankayaTurkey

Personalised recommendations