1932

Abstract

Endothelial cell (EC) metabolism is important for health and disease. Metabolic pathways, such as glycolysis, fatty acid oxidation, and amino acid metabolism, determine vasculature formation. These metabolic pathways have different roles in securing the production of energy and biomass and the maintenance of redox homeostasis in vascular migratory tip cells, proliferating stalk cells, and quiescent phalanx cells, respectively. Emerging evidence demonstrates that perturbation of EC metabolism results in EC dysfunction and vascular pathologies. Here, we summarize recent insights into EC metabolic pathways and their deregulation in vascular diseases. We further discuss the therapeutic implications of targeting EC metabolism in various pathologies.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-020518-114731
2019-02-10
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/physiol/81/1/annurev-physiol-020518-114731.html?itemId=/content/journals/10.1146/annurev-physiol-020518-114731&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Änggård EE. 1990. The endothelium—the body's largest endocrine gland?. J. Endocrinol. 127:3371–75
    [Google Scholar]
  2. 2.  Potente M, Carmeliet P 2017. The link between angiogenesis and endothelial metabolism. Annu. Rev. Physiol. 79:43–66
    [Google Scholar]
  3. 3.  Rafii S, Butler JM, Ding BS 2016. Angiocrine functions of organ-specific endothelial cells. Nature 529:7586316–25
    [Google Scholar]
  4. 4.  Cahill PA, Redmond EM 2016. Vascular endothelium—gatekeeper of vessel health. Atherosclerosis 248:97–109
    [Google Scholar]
  5. 5.  Potente M, Gerhardt H, Carmeliet P 2011. Basic and therapeutic aspects of angiogenesis. Cell 146:6873–87
    [Google Scholar]
  6. 6.  Carmeliet P, Jain RK 2011. Molecular mechanisms and clinical applications of angiogenesis. Nature 473:7347298–307
    [Google Scholar]
  7. 7.  Eelen G, Cruys B, Welti J, De Bock K, Carmeliet P 2013. Control of vessel sprouting by genetic and metabolic determinants. Trends Endocrinol. Metab. 24:12589–96
    [Google Scholar]
  8. 8.  Eelen G, de Zeeuw P, Simons M, Carmeliet P 2015. Endothelial cell metabolism in normal and diseased vasculature. Circ. Res. 116:71231–44
    [Google Scholar]
  9. 9.  Mather KJ. 2013. The vascular endothelium in diabetes—a therapeutic target?. Rev. Endocr. Metab. Disord. 14:187–99
    [Google Scholar]
  10. 10.  De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW et al. 2013. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154:3651–63
    [Google Scholar]
  11. 11.  De Bock K, Georgiadou M, Carmeliet P 2013. Role of endothelial cell metabolism in vessel sprouting. Cell Metab 18:5634–47
    [Google Scholar]
  12. 12.  Helmlinger G, Endo M, Ferrara N, Hlatky L, Jain RK 2000. Formation of endothelial cell networks. Nature 405:6783139–41
    [Google Scholar]
  13. 13.  Uldry M, Thorens B 2004. The SLC2 family of facilitated hexose and polyol transporters. Pflügers Arch. Eur. J. Physiol. 447:5480–89
    [Google Scholar]
  14. 14.  Yu P, Wilhelm K, Dubrac A, Tung JK, Alves TC et al. 2017. FGF-dependent metabolic control of vascular development. Nature 545:7653224–28
    [Google Scholar]
  15. 15.  Vizán P, Sánchez-Tena S, Alcarraz-Vizán G, Soler M, Messeguer R et al. 2009. Characterization of the metabolic changes underlying growth factor angiogenic activation: identification of new potential therapeutic targets. Carcinogenesis 30:6946–52
    [Google Scholar]
  16. 16.  Schoors S, De Bock K, Cantelmo AR, Georgiadou M, Ghesquière B et al. 2014. Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell Metab 19:137–48
    [Google Scholar]
  17. 17.  Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM et al. 2013. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155:2397–409
    [Google Scholar]
  18. 18.  Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC 2008. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452:7184181–86
    [Google Scholar]
  19. 19.  Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S et al. 2009. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci. Signal. 2:97ra73
    [Google Scholar]
  20. 20.  Boeckel JN, Derlet A, Glaser SF, Luczak A, Lucas T et al. 2016. JMJD8 regulates angiogenic sprouting and cellular metabolism by interacting with pyruvate kinase M2 in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 36:71425–33
    [Google Scholar]
  21. 21.  Gupta V, Bamezai RN 2010. Human pyruvate kinase M2: a multifunctional protein. Protein Sci. Publ. Protein Soc. 19:112031–44
    [Google Scholar]
  22. 22.  Wilhelm K, Happel K, Eelen G, Schoors S, Oellerich MF et al. 2016. FOXO1 couples metabolic activity and growth state in the vascular endothelium. Nature 529:7585216–20
    [Google Scholar]
  23. 23.  Doddaballapur A, Michalik KM, Manavski Y, Lucas T, Houtkooper RH et al. 2015. Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3. Arterioscler. Thromb. Vasc. Biol. 35:1137–45
    [Google Scholar]
  24. 24.  Niimi K, Ueda M, Fukumoto M, Kohara M, Sawano T et al. 2017. Transcription factor FOXO1 promotes cell migration toward exogenous ATP via controlling P2Y1 receptor expression in lymphatic endothelial cells. Biochem. Biophys. Res. Commun. 489:4413–19
    [Google Scholar]
  25. 25.  DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB 2008. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:111–20
    [Google Scholar]
  26. 26.  Vander Heiden MG, Cantley LC, Thompson CB 2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:59301029–33
    [Google Scholar]
  27. 27.  Jongkind JF, Verkerk A, Baggen RG 1989. Glutathione metabolism of human vascular endothelial cells under peroxidative stress. Free Radic. Biol. Med. 7:5507–12
    [Google Scholar]
  28. 28.  Ghesquière B, Wong BW, Kuchnio A, Carmeliet P 2014. Metabolism of stromal and immune cells in health and disease. Nature 511:7508167–76
    [Google Scholar]
  29. 29.  Lorenzi M. 2007. The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. Exp. Diabetes Res. 2007:61038
    [Google Scholar]
  30. 30.  Pandolfi PP, Sonati F, Rivi R, Mason P, Grosveld F, Luzzatto L 1995. Targeted disruption of the housekeeping gene encoding glucose 6-phosphate dehydrogenase (G6PD): G6PD is dispensable for pentose synthesis but essential for defense against oxidative stress. EMBO J 14:215209–15
    [Google Scholar]
  31. 31.  Wells L, Vosseller K, Hart GW 2001. Glycosylation of nucleocytoplasmic proteins: signal transduction and O-GlcNAc. Science 291:55122376–78
    [Google Scholar]
  32. 32.  Vosseller K, Sakabe K, Wells L, Hart GW 2002. Diverse regulation of protein function by O-GlcNAc: a nuclear and cytoplasmic carbohydrate post-translational modification. Curr. Opin. Chem. Biol. 6:6851–57
    [Google Scholar]
  33. 33.  Croci DO, Cerliani JP, Dalotto-Moreno T, Méndez-Huergo SP, Mascanfroni ID et al. 2014. Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell 156:4744–58
    [Google Scholar]
  34. 34.  Rahimi N, Costello CE 2015. Emerging roles of post-translational modifications in signal transduction and angiogenesis. Proteomics 15:2–3300–9
    [Google Scholar]
  35. 35.  Luo B, Soesanto Y, McClain DA 2008. Protein modification by O-linked GlcNAc reduces angiogenesis by inhibiting Akt activity in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 28:4651–57
    [Google Scholar]
  36. 36.  Ngoh GA, Facundo HT, Zafir A, Jones SP 2010. O-GlcNAc signaling in the cardiovascular system. Circ. Res. 107:2171–85
    [Google Scholar]
  37. 37.  Hülsmann WC, Dubelaar ML 1988. Aspects of fatty acid metabolism in vascular endothelial cells. Biochimie 70:5681–86
    [Google Scholar]
  38. 38.  Schoors S, Bruning U, Missiaen R, Queiroz KC, Borgers G et al. 2015. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520:7546192–97
    [Google Scholar]
  39. 39.  Kerner J, Hoppel C 2000. Fatty acid import into mitochondria. Biochim. Biophys. Acta 1486:11–17
    [Google Scholar]
  40. 40.  Elmasri H, Ghelfi E, Yu CW, Traphagen S, Cernadas M et al. 2012. Endothelial cell-fatty acid binding protein 4 promotes angiogenesis: role of stem cell factor/c-kit pathway. Angiogenesis 15:3457–68
    [Google Scholar]
  41. 41.  Elmasri H, Karaaslan C, Teper Y, Ghelfi E, Weng M et al. 2009. Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cells. FASEB J 23:113865–73
    [Google Scholar]
  42. 42.  Harjes U, Bridges E, McIntyre A, Fielding BA, Harris AL 2014. Fatty acid-binding protein 4, a point of convergence for angiogenic and metabolic signaling pathways in endothelial cells. J. Biol. Chem. 289:3323168–76
    [Google Scholar]
  43. 43.  Harjes U, Kalucka J, Carmeliet P 2016. Targeting fatty acid metabolism in cancer and endothelial cells. Crit. Rev. Oncol. Hematol. 97:15–21
    [Google Scholar]
  44. 44.  Iso T, Maeda K, Hanaoka H, Suga T, Goto K et al. 2013. Capillary endothelial fatty acid binding proteins 4 and 5 play a critical role in fatty acid uptake in heart and skeletal muscle. Arterioscler. Thromb. Vasc. Biol. 33:112549–57
    [Google Scholar]
  45. 45.  Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J et al. 2010. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464:7290917–21
    [Google Scholar]
  46. 46.  Dijkstra MH, Pirinen E, Huusko J, Kivelä R, Schenkwein D et al. 2014. Lack of cardiac and high-fat diet induced metabolic phenotypes in two independent strains of Vegf-b knockout mice. Sci. Rep. 4:6238
    [Google Scholar]
  47. 47.  Kivelä R, Bry M, Robciuc MR, Räsänen M, Taavitsainen M et al. 2014. VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart. EMBO Mol. Med. 6:3307–21
    [Google Scholar]
  48. 48.  Davies BSJ, Goulbourne CN, Barnes RH 2nd, Turlo KA, Gin P et al. 2012. Assessing mechanisms of GPIHBP1 and lipoprotein lipase movement across endothelial cells. J. Lipid Res. 53:122690–97
    [Google Scholar]
  49. 49.  Patella F, Schug ZT, Persi E, Neilson LJ, Erami Z et al. 2015. Proteomics-based metabolic modeling reveals that fatty acid oxidation (FAO) controls endothelial cell (EC) permeability. Mol. Cell. Proteom. 14:3621–34
    [Google Scholar]
  50. 50.  Wong BW, Wang X, Zecchin A, Thienpont B, Cornelissen I et al. 2017. The role of fatty acid β-oxidation in lymphangiogenesis. Nature 542:763949–54
    [Google Scholar]
  51. 51.  Huang H, Vandekeere S, Kalucka J, Bierhansl L, Zecchin A et al. 2017. Role of glutamine and interlinked asparagine metabolism in vessel formation. EMBO J 36:162334–52
    [Google Scholar]
  52. 52.  Kim B, Li J, Jang C, Arany Z 2017. Glutamine fuels proliferation but not migration of endothelial cells. EMBO J 36:162321–33
    [Google Scholar]
  53. 53.  Newsholme P, Procopio J, Lima MM, Pithon-Curi TC, Curi R 2003. Glutamine and glutamate—their central role in cell metabolism and function. Cell Biochem. Funct. 21:11–9
    [Google Scholar]
  54. 54.  Krützfeldt A, Spahr R, Mertens S, Siegmund B, Piper HM 1990. Metabolism of exogenous substrates by coronary endothelial cells in culture. J. Mol. Cell. Cardiol. 22:121393–404
    [Google Scholar]
  55. 55.  DeBerardinis RJ, Cheng T 2010. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29:3313–24
    [Google Scholar]
  56. 56.  Kucharzewska P, Welch JE, Svensson KJ, Belting M 2010. Ornithine decarboxylase and extracellular polyamines regulate microvascular sprouting and actin cytoskeleton dynamics in endothelial cells. Exp. Cell Res. 316:162683–91
    [Google Scholar]
  57. 57.  Matsunaga T, Weihrauch DW, Moniz MC, Tessmer J, Warltier DC, Chilian WM 2002. Angiostatin inhibits coronary angiogenesis during impaired production of nitric oxide. Circulation 105:182185–91
    [Google Scholar]
  58. 58.  Harrison DG. 1997. Cellular and molecular mechanisms of endothelial cell dysfunction. J. Clin. Investig. 100:92153–57
    [Google Scholar]
  59. 59.  Morris SM Jr 2009. Recent advances in arginine metabolism: roles and regulation of the arginases. Br. J. Pharmacol. 157:6922–30
    [Google Scholar]
  60. 60.  Palmer RM, Ashton DS, Moncada S 1988. Vascular endothelial cells synthesize nitric oxide from l-arginine. Nature 333:6174664–66
    [Google Scholar]
  61. 61.  Kovamees O, Shemyakin A, Eriksson M, Angelin B, Pernow J 2016. Arginase inhibition improves endothelial function in patients with familial hypercholesterolaemia irrespective of their cholesterol levels. J. Intern. Med. 279:5477–84
    [Google Scholar]
  62. 62.  Villalba N, Sackheim AM, Nunez IA, Hill-Eubanks DC, Nelson MT et al. 2017. Traumatic brain injury causes endothelial dysfunction in the systemic microcirculation through arginase-1-dependent uncoupling of endothelial nitric oxide synthase. J. Neurotrauma 34:1192–203
    [Google Scholar]
  63. 63.  Amelio I, Cutruzzola F, Antonov A, Agostini M, Melino G 2014. Serine and glycine metabolism in cancer. Trends Biochem. Sci. 39:4191–98
    [Google Scholar]
  64. 64.  Tibbetts AS, Appling DR 2010. Compartmentalization of mammalian folate-mediated one-carbon metabolism. Annu. Rev. Nutr. 30:57–81
    [Google Scholar]
  65. 65.  Mozaffarian D. 2016. Natural trans fat, dairy fat, partially hydrogenated oils, and cardiometabolic health: the Ludwigshafen Risk and Cardiovascular Health Study. Eur. Heart J. 37:131079–81
    [Google Scholar]
  66. 66.  Libby P, Bornfeldt KE, Tall AR 2016. Atherosclerosis: successes, surprises, and future challenges. Circ. Res. 118:4531–34
    [Google Scholar]
  67. 67.  Gimbrone MA Jr, García-Cardeña G. 2016. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ. Res. 118:4620–36
    [Google Scholar]
  68. 68.  Davignon J, Ganz P 2004. Role of endothelial dysfunction in atherosclerosis. Circulation 109:23III27–32
    [Google Scholar]
  69. 69.  Kawashima S, Yokoyama M 2004. Dysfunction of endothelial nitric oxide synthase and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 24:6998–1005
    [Google Scholar]
  70. 70.  Napoli C, Ignarro LJ 2007. Polymorphisms in endothelial nitric oxide synthase and carotid artery atherosclerosis. J. Clin. Pathol. 60:4341–44
    [Google Scholar]
  71. 71.  Baum C, Johannsen SS, Zeller T, Atzler D, Ojeda FM et al. 2016. ADMA and arginine derivatives in relation to non-invasive vascular function in the general population. Atherosclerosis 244:149–56
    [Google Scholar]
  72. 72.  Notsu Y, Yano S, Shibata H, Nagai A, Nabika T 2015. Plasma arginine/ADMA ratio as a sensitive risk marker for atherosclerosis: Shimane CoHRE study. Atherosclerosis 239:161–66
    [Google Scholar]
  73. 73.  Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP 1999. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 99:243092–95
    [Google Scholar]
  74. 74.  Pope AJ, Druhan L, Guzman JE, Forbes SP, Murugesan V et al. 2007. Role of DDAH-1 in lipid peroxidation product-mediated inhibition of endothelial NO generation. Am. J. Physiol. Cell Physiol. 293:5C1679–86
    [Google Scholar]
  75. 75.  Dowsett L, Piper S, Slaviero A, Dufton N, Wang Z et al. 2015. Endothelial dimethylarginine dimethylaminohydrolase 1 is an important regulator of angiogenesis but does not regulate vascular reactivity or hemodynamic homeostasis. Circulation 131:2217–25
    [Google Scholar]
  76. 76.  Bogdanski P, Suliburska J, Szulinska M, Sikora M, Walkowiak J, Jakubowski H 2015. l-arginine and vitamin C attenuate pro-atherogenic effects of high-fat diet on biomarkers of endothelial dysfunction in rats. Biomed. Pharmacother. 76:100–6
    [Google Scholar]
  77. 77.  Loscalzo J. 2003. Adverse effects of supplemental l-arginine in atherosclerosis: consequences of methylation stress in a complex catabolism?. Arterioscler. Thromb. Vasc. Biol. 23:13–5
    [Google Scholar]
  78. 78.  Menghini R, Casagrande V, Cardellini M, Ballanti M, Davato F et al. 2015. FoxO1 regulates asymmetric dimethylarginine via downregulation of dimethylaminohydrolase 1 in human endothelial cells and subjects with atherosclerosis. Atherosclerosis 242:1230–35
    [Google Scholar]
  79. 79.  Tsuchiya K, Tanaka J, Shuiqing Y, Welch CL, DePinho RA et al. 2012. FoxOs integrate pleiotropic actions of insulin in vascular endothelium to protect mice from atherosclerosis. Cell Metab 15:3372–81
    [Google Scholar]
  80. 80.  Xiao Y, Huang W, Zhang J, Peng C, Xia M, Ling W 2015. Increased plasma S-adenosylhomocysteine-accelerated atherosclerosis is associated with epigenetic regulation of endoplasmic reticulum stress in apoE−/− mice. Arterioscler. Thromb. Vasc. Biol. 35:160–70
    [Google Scholar]
  81. 81.  Wu S, Gao X, Yang S, Meng M, Yang X, Ge B 2015. The role of endoplasmic reticulum stress in endothelial dysfunction induced by homocysteine thiolactone. Fundam. Clin. Pharmacol. 29:3252–59
    [Google Scholar]
  82. 82.  Zhang H, Liu Z, Ma S, Zhang H, Kong F et al. 2016. Ratio of S-adenosylmethionine to S-adenosylhomocysteine as a sensitive indicator of atherosclerosis. Mol. Med. Rep. 14:1289–300
    [Google Scholar]
  83. 83.  Rabelo LA, Ferreira FO, Nunes-Souza V, da Fonseca LJ, Goulart MO 2015. Arginase as a critical prooxidant mediator in the binomial endothelial dysfunction-atherosclerosis. Oxidative Med. Cell. Longev. 2015:924860
    [Google Scholar]
  84. 84.  Steppan J, Nyhan D, Berkowitz DE 2013. Development of novel arginase inhibitors for therapy of endothelial dysfunction. Front. Immunol. 4:278
    [Google Scholar]
  85. 85.  de Bruin RG, van der Veer EP, Prins J, Lee DH, Dane MJ et al. 2016. The RNA-binding protein quaking maintains endothelial barrier function and affects VE-cadherin and β-catenin protein expression. Sci. Rep. 6:21643
    [Google Scholar]
  86. 86.  Novodvorsky P, Chico TJ 2014. The role of the transcription factor KLF2 in vascular development and disease. Prog. Mol. Biol. Transl. Sci. 124:155–88
    [Google Scholar]
  87. 87.  Loyer X, Potteaux S, Vion AC, Guerin CL, Boulkroun S et al. 2014. Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice. Circ. Res. 114:3434–43
    [Google Scholar]
  88. 88.  Tanweer O, Wilson TA, Metaxa E, Riina HA, Meng H 2014. A comparative review of the hemodynamics and pathogenesis of cerebral and abdominal aortic aneurysms: lessons to learn from each other. J. Cerebrovasc. Endovasc. Neurosurg. 16:4335–49
    [Google Scholar]
  89. 89.  McCormick ML, Gavrila D, Weintraub NL 2007. Role of oxidative stress in the pathogenesis of abdominal aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 27:3461–69
    [Google Scholar]
  90. 90.  Fan LM, Douglas G, Bendall JK, McNeill E, Crabtree MJ et al. 2014. Endothelial cell-specific reactive oxygen species production increases susceptibility to aortic dissection. Circulation 129:252661–72
    [Google Scholar]
  91. 91.  Wasserman DH, Wang TJ, Brown NJ 2018. The vasculature in prediabetes. Circ. Res. 122:81135–50
    [Google Scholar]
  92. 92.  Hamilton SJ, Watts GF 2013. Endothelial dysfunction in diabetes: pathogenesis, significance, and treatment. Rev. Diabet. Stud. 10:2–3133–56
    [Google Scholar]
  93. 93.  Kolluru GK, Bir SC, Kevil CG 2012. Endothelial dysfunction and diabetes: effects on angiogenesis, vascular remodeling, and wound healing. Int. J. Vasc. Med. 2012:918267
    [Google Scholar]
  94. 94.  Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE et al. 2000. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321:7258405–12
    [Google Scholar]
  95. 95.  Eelen G, de Zeeuw P, Treps L, Harjes U, Wong BW, Carmeliet P 2018. Endothelial cell metabolism. Physiol. Rev. 98:13–58
    [Google Scholar]
  96. 96.  Guzik TJ, Mussa S, Gastaldi D, Sadowski J, Ratnatunga C et al. 2002. Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 105:141656–62
    [Google Scholar]
  97. 97.  Liu J, Wang C, Liu F, Lu Y, Cheng J 2015. Metabonomics revealed xanthine oxidase-induced oxidative stress and inflammation in the pathogenesis of diabetic nephropathy. Anal. Bioanal. Chem. 407:92569–79
    [Google Scholar]
  98. 98.  Shevalye H, Lupachyk S, Watcho P, Stavniichuk R, Khazim K et al. 2012. Prediabetic nephropathy as an early consequence of the high-calorie/high-fat diet: relation to oxidative stress. Endocrinology 153:31152–61
    [Google Scholar]
  99. 99.  Sasaki N, Yamashita T, Takaya T, Shinohara M, Shiraki R et al. 2008. Augmentation of vascular remodeling by uncoupled endothelial nitric oxide synthase in a mouse model of diabetes mellitus. Arterioscler. Thromb. Vasc. Biol. 28:61068–76
    [Google Scholar]
  100. 100.  Su Y, Qadri SM, Hossain M, Wu L, Liu L 2013. Uncoupling of eNOS contributes to redox-sensitive leukocyte recruitment and microvascular leakage elicited by methylglyoxal. Biochem. Pharmacol. 86:121762–74
    [Google Scholar]
  101. 101.  Tang X, Luo YX, Chen HZ, Liu DP 2014. Mitochondria, endothelial cell function, and vascular diseases. Front. Physiol. 5:175
    [Google Scholar]
  102. 102.  Ceolotto G, Gallo A, Papparella I, Franco L, Murphy E et al. 2007. Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD(P)H oxidase via AMPK-dependent mechanism. Arterioscler. Thromb. Vasc. Biol. 27:122627–33
    [Google Scholar]
  103. 103.  Wang XR, Zhang MW, Chen DD, Zhang Y, Chen AF 2011. AMP-activated protein kinase rescues the angiogenic functions of endothelial progenitor cells via manganese superoxide dismutase induction in type 1 diabetes. Am. J. Physiol. Endocrinol. Metab. 300:6E1135–45
    [Google Scholar]
  104. 104.  Kukidome D, Nishikawa T, Sonoda K, Imoto K, Fujisawa K et al. 2006. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 55:1120–27
    [Google Scholar]
  105. 105.  Li FY, Lam KS, Tse HF, Chen C, Wang Y et al. 2012. Endothelium-selective activation of AMP-activated protein kinase prevents diabetes mellitus-induced impairment in vascular function and reendothelialization via induction of heme oxygenase-1 in mice. Circulation 126:101267–77
    [Google Scholar]
  106. 106.  Dinkova-Kostova AT, Abramov AY 2015. The emerging role of Nrf2 in mitochondrial function. Free Radic. Biol. Med. 88:Part B179–88
    [Google Scholar]
  107. 107.  Xue M, Rabbani N, Momiji H, Imbasi P, Anwar MM et al. 2012. Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation. Biochem. J. 443:1213–22
    [Google Scholar]
  108. 108.  Brouwers O, Niessen PM, Miyata T, Østergaard JA, Flyvbjerg A et al. 2014. Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes. Diabetologia 57:1224–35
    [Google Scholar]
  109. 109.  Mo C, Wang L, Zhang J, Numazawa S, Tang H et al. 2014. The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice. Antioxid. Redox Signal. 20:4574–88
    [Google Scholar]
  110. 110.  Paneni F, Costantino S, Cosentino F 2015. Role of oxidative stress in endothelial insulin resistance. World J. Diabetes 6:2326–32
    [Google Scholar]
  111. 111.  Kaiser N, Sasson S, Feener EP, Boukobza-Vardi N, Higashi S et al. 1993. Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells. Diabetes 42:180–89
    [Google Scholar]
  112. 112.  Wei X, Schneider JG, Shenouda SM, Lee A, Towler DA et al. 2011. De novo lipogenesis maintains vascular homeostasis through endothelial nitric-oxide synthase (eNOS) palmitoylation. J. Biol. Chem. 286:42933–45
    [Google Scholar]
  113. 113.  Wei X, Song H, Semenkovich CF 2014. Insulin-regulated protein palmitoylation impacts endothelial cell function. Arterioscler. Thromb. Vasc. Biol. 34:2346–54
    [Google Scholar]
  114. 114.  Jang C, Oh SF, Wada S, Rowe GC, Liu L et al. 2016. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat. Med. 22:421–26
    [Google Scholar]
  115. 115.  Khitan Z, Kim DH 2013. Fructose: a key factor in the development of metabolic syndrome and hypertension. J. Nutr. Metab. 2013:682673
    [Google Scholar]
  116. 116.  Cirillo P, Pellegrino G, Conte S, Maresca F, Pacifico F et al. 2015. Fructose induces prothrombotic phenotype in human endothelial cells: a new role for “added sugar” in cardio-metabolic risk. J. Thromb. Thrombolysis 40:444–51
    [Google Scholar]
  117. 117.  Jain RK. 2014. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26:5605–22
    [Google Scholar]
  118. 118.  Krock BL, Skuli N, Simon MC 2011. Hypoxia-induced angiogenesis: good and evil. Genes Cancer 2:121117–33
    [Google Scholar]
  119. 119.  Hida K, Maishi N, Sakurai Y, Hida Y, Harashima H 2016. Heterogeneity of tumor endothelial cells and drug delivery. Adv. Drug Deliv. Rev. 99:Part B140–47
    [Google Scholar]
  120. 120.  Cantelmo AR, Conradi LC, Brajic A, Goveia J, Kalucka J et al. 2016. Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy. Cancer Cell 30:6968–85
    [Google Scholar]
  121. 121.  van Beijnum JR, Dings RP, van der Linden E, Zwaans BM, Ramaekers FC et al. 2006. Gene expression of tumor angiogenesis dissected: specific targeting of colon cancer angiogenic vasculature. Blood 108:72339–48
    [Google Scholar]
  122. 122.  Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O 2011. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis. Cancer Res 71:72550–60
    [Google Scholar]
  123. 123.  Lee DC, Sohn HA, Park ZY, Oh S, Kang YK et al. 2015. A lactate-induced response to hypoxia. Cell 161:3595–609
    [Google Scholar]
  124. 124.  Wenes M, Shang M, Di Matteo M, Goveia J, Martin-Pérez R et al. 2016. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab 24:701–15
    [Google Scholar]
  125. 125.  Rivera JC, Dabouz R, Noueihed B, Omri S, Tahiri H, Chemtob S 2017. Ischemic retinopathies: oxidative stress and inflammation. Oxidative Med. Cell. Longev. 2017:3940241
    [Google Scholar]
  126. 126.  Wong WL, Su X, Li X, Cheung CM, Klein R et al. 2014. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Global Health 2:2e106–16
    [Google Scholar]
  127. 127.  Shah GN, Price TO, Banks WA, Morofuji Y, Kovac A et al. 2013. Pharmacological inhibition of mitochondrial carbonic anhydrases protects mouse cerebral pericytes from high glucose-induced oxidative stress and apoptosis. J. Pharmacol. Exp. Ther. 344:3637–45
    [Google Scholar]
  128. 128.  Dodson MW, Brown LM, Elliott CG 2018. Pulmonary arterial hypertension. Heart Failure Clin 14:3255–69
    [Google Scholar]
  129. 129.  Leopold JA, Maron BA 2016. Molecular mechanisms of pulmonary vascular remodeling in pulmonary arterial hypertension. Int. J. Mol. Sci. 17:5761
    [Google Scholar]
  130. 130.  Thenappan T, Prins KW, Cogswell R, Shah SJ 2015. Pulmonary hypertension secondary to heart failure with preserved ejection fraction. Can. J. Cardiol. 31:4430–39
    [Google Scholar]
  131. 131.  Rafikova O, Srivastava A, Desai AA, Rafikov R, Tofovic SP 2018. Recurrent inhibition of mitochondrial complex III induces chronic pulmonary vasoconstriction and glycolytic switch in the rat lung. Respir. Res. 19:169
    [Google Scholar]
  132. 132.  Bertero T, Oldham WM, Cottrill KA, Pisano S, Vanderpool RR et al. 2016. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J. Clin. Investig. 126:93313–35
    [Google Scholar]
  133. 133.  Brittain EL, Talati M, Fessel JP, Zhu H, Penner N et al. 2016. Fatty acid metabolic defects and right ventricular lipotoxicity in human pulmonary arterial hypertension. Circulation 133:201936–44
    [Google Scholar]
  134. 134.  Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R et al. 1993. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N. Engl. J. Med. 328:241732–39
    [Google Scholar]
  135. 135.  Ghosh S, Gupta M, Xu W, Mavrakis DA, Janocha AJ et al. 2016. Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 310:11L1199–205
    [Google Scholar]
  136. 136.  Garrigue P, Bodin-Hullin A, Balasse L, Fernandez S, Essamet W et al. 2017. The evolving role of succinate in tumor metabolism: an 18F-FDG–based study. J. Nuclear Med. 58:111749–55
    [Google Scholar]
  137. 137.  Zhang D, Wang Y, Shi Z, Liu J, Sun P et al. 2015. Metabolic reprogramming of cancer-associated fibroblasts by IDH3α downregulation. Cell Rep 10:81335–48
    [Google Scholar]
  138. 138.  Dong L, Krewson EA, Yang LV 2017. Acidosis activates endoplasmic reticulum stress pathways through GPR4 in human vascular endothelial cells. Int. J. Mol. Sci. 18:2278
    [Google Scholar]
  139. 139.  Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM et al. 2014. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:7519559–63
    [Google Scholar]
  140. 140.  Castegna A, Menga A 2018. Glutamine synthetase: localization dictates outcome. Genes 9:2108
    [Google Scholar]
  141. 141.  Pisarsky L, Bill R, Fagiani E, Dimeloe S, Goosen RW et al. 2016. Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy. Cell Rep 15:61161–74
    [Google Scholar]
  142. 142.  Yang J, Ruchti E, Petit JM, Jourdain P, Grenningloh G et al. 2014. Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons. PNAS 111:3312228–33
    [Google Scholar]
  143. 143.  Becker JC, Andersen MH, Schrama D, thor Straten P 2013. Immune-suppressive properties of the tumor microenvironment. Cancer Immunol. Immunother. 62:71137–48
    [Google Scholar]
  144. 144.  Colombo M, Raposo G, Théry C 2014. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30:255–89
    [Google Scholar]
  145. 145.  Garcia NA, Moncayo-Arlandi J, Sepulveda P, Diez-Juan A 2016. Cardiomyocyte exosomes regulate glycolytic flux in endothelium by direct transfer of GLUT transporters and glycolytic enzymes. Cardiovasc. Res. 109:3397–408
    [Google Scholar]
  146. 146.  Bergers G, Hanahan D 2008. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8:8592–603
    [Google Scholar]
  147. 147.  Qu Q, Zeng F, Liu X, Wang QJ, Deng F 2016. Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer. Cell Death Dis 7:e2226
    [Google Scholar]
  148. 148.  Ashrafian H, Horowitz JD, Frenneaux MP 2007. Perhexiline. Cardiovasc. Drug Rev. 25:176–97
    [Google Scholar]
  149. 149.  Gross MI, Demo SD, Dennison JB, Chen L, Chernov-Rogan T et al. 2014. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol. Cancer Ther. 13:4890–901
    [Google Scholar]
  150. 150.  Jacque N, Ronchetti AM, Larrue C, Meunier G, Birsen R et al. 2015. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood 126:111346–56
    [Google Scholar]
  151. 151.  Ikeuchi H, Ahn YM, Otokawa T, Watanabe B, Hegazy L et al. 2012. A sulfoximine-based inhibitor of human asparagine synthetase kills l-asparaginase-resistant leukemia cells. Bioorg. Med. Chem. 20:195915–27
    [Google Scholar]
/content/journals/10.1146/annurev-physiol-020518-114731
Loading
/content/journals/10.1146/annurev-physiol-020518-114731
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error