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Frontiers in Biology

, Volume 10, Issue 2, pp 125–140 | Cite as

Targeting endothelial cell metabolism: new therapeutic prospects?

  • Annalisa Zecchin
  • Aleksandra Brajic
  • Peter CarmelietEmail author
Review
  • 277 Downloads

Abstract

Endothelial cells (ECs) line blood vessels and function as a vital conduit for oxygen and nutrients, but can also form vascular niches for various types of stem cells. While mostly quiescent throughout adult life, ECs can rapidly switch to a highly active state, and start to sprout in order to form new blood vessels. ECs can also become dysfunctional, as occurs in diabetes and atherosclerosis. Recent studies have demonstrated a key role for EC metabolism in the regulation of angiogenesis, and showed that EC metabolism is even capable of overriding genetic signals. In this review, we will review the basic principles of EC metabolism and focus on the metabolic alterations that accompany EC dysfunction in diabetes and vessel overgrowth in cancer. We will also highlight how EC metabolism influences EC behavior by modulating post-translational modification and epigenetic changes, and illustrate how dietary supplementation of metabolites can change EC responses. Finally, we will discuss the potential of targeting EC metabolism as a novel therapeutic strategy.

Keywords

angiogenesis metabolism endothelial cell dysfunction anti-angiogenic therapy 

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References

  1. Akinyeke T, Matsumura S, Wang X, Wu Y, Schalfer E D, Saxena A, Yan W, Logan S K, Li X (2013). Metformin targets c-MYC oncogene to prevent prostate cancer. Carcinogenesis, 34(12): 2823–2832PubMedCentralPubMedGoogle Scholar
  2. Algire C, Amrein L, Bazile M, David S, Zakikhani M, Pollak M (2011). Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene, 30(10): 1174–1182PubMedGoogle Scholar
  3. Antonetti D A, Klein R, Gardner T W (2012). Diabetic retinopathy. N Engl J Med, 366(13): 1227–1239PubMedGoogle Scholar
  4. Antoniades C, Bakogiannis C, Leeson P, Guzik T J, Zhang M H, Tousoulis D, Antonopoulos A S, Demosthenous M, Marinou K, Hale A, Paschalis A, Psarros C, Triantafyllou C, Bendall J, Casadei B, Stefanadis C, Channon K M (2011). Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling. Circulation, 124(3): 335–345PubMedGoogle Scholar
  5. Arany Z, Foo S Y, Ma Y, Ruas J L, Bommi-Reddy A, Girnun G, Cooper M, Laznik D, Chinsomboon J, Rangwala S M, Baek K H, Rosenzweig A, Spiegelman BM (2008). HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature, 451(7181): 1008–1012PubMedGoogle Scholar
  6. Arunachalam G, Samuel S M, Marei I, Ding H, Triggle C R (2014). Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1. Br J Pharmacol, 171(2): 523–535PubMedCentralPubMedGoogle Scholar
  7. Avraham-Davidi I, Ely Y, Pham V N, Castranova D, Grunspan M, Malkinson G, Gibbs-Bar L, Mayseless O, Allmog G, Lo B, Warren C M, Chen T T, Ungos J, Kidd K, Shaw K, Rogachev I, Wan W, Murphy P M, Farber S A, Carmel L, Shelness G S, Iruela-Arispe M L, Weinstein B M, Yaniv K (2012). ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1. Nat Med, 18(6): 967–973PubMedCentralPubMedGoogle Scholar
  8. Batchuluun B, Inoguchi T, Sonoda N, Sasaki S, Inoue T, Fujimura Y, Miura D, Takayanagi R (2014). Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P) H oxidase pathway in human aortic endothelial cells. Atherosclerosis, 232(1): 156–164PubMedGoogle Scholar
  9. Beleznai T, Bagi Z (2012). Activation of hexosamine pathway impairs nitric oxide (NO)-dependent arteriolar dilations by increased protein O-GlcNAcylation. Vascul Pharmacol, 56(3–4): 115–121PubMedCentralPubMedGoogle Scholar
  10. Benedito R, Roca C, Sörensen I, Adams S, Gossler A, Fruttiger M, Adams R H (2009). The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell, 137(6): 1124–1135PubMedGoogle Scholar
  11. Biasucci L M, Biasillo G, Stefanelli A (2010). Inflammatory markers, cholesterol and statins: pathophysiological role and clinical importance. Clin Chem Lab Med, 48: 1685–1691PubMedGoogle Scholar
  12. Bode-Böger SM, Scalera F, Ignarro L J (2007). The L-arginine paradox: Importance of the L-arginine/asymmetrical dimethylarginine ratio. Pharmacol Ther, 114(3): 295–306PubMedGoogle Scholar
  13. Boger R H (2009). Asymmetric dimethylarginine: understanding the physiology, genetics, and clinical relevance of this novel biomarker. Proceedings of the 4th International Symposium on ADMA. Pharmacol Res, 60: 447Google Scholar
  14. Brandes R P, Weissmann N, Schröder K (2014). Redox-mediated signal transduction by cardiovascular Nox NADPH oxidases. J Mol Cell Cardiol, 73: 70–79PubMedGoogle Scholar
  15. Browne C D, Hindmarsh E J, Smith JW (2006). Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor. FASEB J, 20: 2027–2035PubMedGoogle Scholar
  16. Brownlee M (2001). Biochemistry and molecular cell biology of diabetic complications. Nature, 414(6865): 813–820PubMedGoogle Scholar
  17. Brownlee M (2005). The pathobiology of diabetic complications: a unifying mechanism. Diabetes, 54(6): 1615–1625PubMedGoogle Scholar
  18. Cai S, Khoo J, Channon K M (2005). Augmented BH4 by gene transfer restores nitric oxide synthase function in hyperglycemic human endothelial cells. Cardiovasc Res, 65(4): 823–831PubMedGoogle Scholar
  19. Calder P C (2014). Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochim Biophys ActaGoogle Scholar
  20. Calviello G, Di Nicuolo F, Gragnoli S, Piccioni E, Serini S, Maggiano N, Tringali G, Navarra P, Ranelletti F O, Palozza P (2004). n-3 PUFAs reduce VEGF expression in human colon cancer cells modulating the COX-2/PGE2 induced ERK-1 and-2 and HIF-1alpha induction pathway. Carcinogenesis, 25(12): 2303–2310PubMedGoogle Scholar
  21. Carracedo A, Cantley L C, Pandolfi P P (2013). Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer, 13(4): 227–232PubMedCentralPubMedGoogle Scholar
  22. Castillo-Díaz S A, Garay-Sevilla M E, Hernández-González M A, Solís-Martínez M O, Zaina S (2010). Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries. Int J Mol Med, 26(5): 691–700PubMedGoogle Scholar
  23. Chan J R, Böger R H, Bode-Böger SM, Tangphao O, Tsao P S, Blaschke T F, Cooke J P (2000). Asymmetric dimethylarginine increases mononuclear cell adhesiveness in hypercholesterolemic humans. Arterioscler Thromb Vasc Biol, 20(4): 1040–1046PubMedGoogle Scholar
  24. Cho Y E, Basu A, Dai A, Heldak M, Makino A (2013). Coronary endothelial dysfunction and mitochondrial reactive oxygen species in type 2 diabetic mice. Am J Physiol Cell Physiol, 305(10): C1033–C1040PubMedCentralPubMedGoogle Scholar
  25. Choudhary C, Weinert B T, Nishida Y, Verdin E, Mann M (2014). The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol, 15(8): 536–550PubMedGoogle Scholar
  26. Chung S J, Lee S H, Lee Y J, Park H S, Bönger R, Kang Y H (2004). Pyruvate protection against endothelial cytotoxicity induced by blockade of glucose uptake. J Biochem Mol Biol, 37(2): 239–245PubMedGoogle Scholar
  27. Cittadini A, Napoli R, Monti M G, Rea D, Longobardi S, Netti P A, Walser M, Samà M, Aimaretti G, Isgaard J, Saccà L (2012). Metformin prevents the development of chronic heart failure in the SHHF rat model. Diabetes, 61(4): 944–953PubMedCentralPubMedGoogle Scholar
  28. Connor K M, SanGiovanni J P, Lofqvist C, Aderman C M, Chen J, Higuchi A, Hong S, Pravda E A, Majchrzak S, Carper D, Hellstrom A, Kang J X, Chew E Y, Salem N Jr, Serhan C N, Smith L E (2007). Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med, 13(7): 868–873PubMedGoogle Scholar
  29. Coutelle O, Hornig-Do H T, Witt A, Andree M, Schiffmann L M, Piekarek M, Brinkmann K, Seeger JM, Liwschitz M, Miwa S, Hallek M, Krönke M, Trifunovic A, Eming S A, Wiesner R J, Hacker U T, Kashkar H (2014). Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing. EMBO Mol Med, 6(5): 624–639PubMedCentralPubMedGoogle Scholar
  30. Crabtree M J, Tatham A L, Al-Wakeel Y, Warrick N, Hale A B, Cai S, Channon K M, Alp N J (2009). Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: insights from cells with tet-regulated GTP cyclohydrolase I expression. J Biol Chem, 284(2): 1136–1144PubMedGoogle Scholar
  31. Croci D O, Cerliani J P, Dalotto-Moreno T, Méndez-Huergo S P, Mascanfroni I D, Dergan-Dylon S, Toscano M A, Caramelo J J, García-Vallejo J J, Ouyang J, Mesri E A, Junttila M R, Bais C, Shipp M A, Salatino M, Rabinovich G A (2014). Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell, 156(4): 744–758PubMedGoogle Scholar
  32. Curtarello M, Zulato E, Nardo G, Valtorta S, Guzzo G, Rossi E, Esposito G, Msaki A, Pastò A, Rasola A, Persano L, Ciccarese F, Bertorelle R, Todde S, Plebani M, Schroer H, Walenta S, Mueller-Klieser W, Amadori A, Moresco R M, Indraccolo S (2015). VEGF-targeted therapy stably modulates the glycolytic phenotype of tumor cells. Cancer Res, 75(1): 120–133PubMedGoogle Scholar
  33. Dagher Z, Ruderman N, Tornheim K, Ido Y (2001). Acute regulation of fatty acid oxidation and amp-activated protein kinase in human umbilical vein endothelial cells. Circ Res, 88(12): 1276–1282PubMedGoogle Scholar
  34. Dallaglio K, Bruno A, Cantelmo A R, Esposito A I, Ruggiero L, Orecchioni S, Calleri A, Bertolini F, Pfeffer U, Noonan D M, Albini A (2014). Paradoxic effects of metformin on endothelial cells and angiogenesis. Carcinogenesis, 35(5): 1055–1066PubMedCentralPubMedGoogle Scholar
  35. Davignon J, Ganz P (2004). Role of endothelial dysfunction in atherosclerosis. Circulation, 109(23 Suppl 1): III27–III32PubMedGoogle Scholar
  36. Davis B J, Xie Z, Viollet B, Zou M H (2006). Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes, 55(2): 496–505PubMedGoogle Scholar
  37. Dawson M A, Kouzarides T (2012). Cancer epigenetics: from mechanism to therapy. Cell, 150(1): 12–27PubMedGoogle Scholar
  38. Dayeh T, Volkov P, Salö S, Hall E, Nilsson E, Olsson A H, Kirkpatrick C L, Wollheim C B, Eliasson L, Rönn T, Bacos K, Ling C (2014). Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet, 10(3): e1004160PubMedCentralPubMedGoogle Scholar
  39. De Bock K, Georgiadou M, Carmeliet P (2013a). Role of endothelial cell metabolism in vessel sprouting. Cell Metab, 18(5): 634–647PubMedGoogle Scholar
  40. De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong B W, Cantelmo A R, Quaegebeur A, Ghesquière B, Cauwenberghs S, Eelen G, Phng L K, Betz I, Tembuyser B, Brepoels K, Welti J, Geudens I, Segura I, Cruys B, Bifari F, Decimo I, Blanco R, Wyns S, Vangindertael J, Rocha S, Collins R T, Munck S, Daelemans D, Imamura H, Devlieger R, Rider M, Van Veldhoven P P, Schuit F, Bartrons R, Hofkens J, Fraisl P, Telang S, Deberardinis R J, Schoonjans L, Vinckier S, Chesney J, Gerhardt H, Dewerchin M, Carmeliet P (2013b). Role of PFKFB3-driven glycolysis in vessel sprouting. Cell, 154(3): 651–663PubMedGoogle Scholar
  41. Dhillon B, Badiwala M V, Maitland A, Rao V, Li S H, Verma S (2003). etrahydrobiopterin attenuates homocysteine induced endothelial dysfunction. Mol Cell Biochem, 247(1–2): 223–227PubMedGoogle Scholar
  42. Doddaballapur A, Michalik K M, Manavski Y, Lucas T, Houtkooper R H, You X, Chen W, Zeiher A M, Potente M, Dimmeler S, Boon R A (2015). Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3. Arterioscler Thromb Vasc Biol, 35(1): 137–145PubMedGoogle Scholar
  43. Dowling R J O, Niraula S, Stambolic V, Goodwin P J (2012). Metformin in cancer: translational challenges. J Mol Endocrinol, 48(3): R31–R43PubMedGoogle Scholar
  44. Du X, Matsumura T, Edelstein D, Rossetti L, Zsengellér Z, Szabó C, Brownlee M (2003). Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest, 112(7): 1049–1057PubMedCentralPubMedGoogle Scholar
  45. Du X L, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M (2001). Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest, 108(9): 1341–1348PubMedCentralPubMedGoogle Scholar
  46. Du X L, Edelstein D, Rossetti L, Fantus I G, Goldberg H, Ziyadeh F, Wu J, Brownlee M (2000). Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA, 97(22): 12222–12226PubMedCentralPubMedGoogle Scholar
  47. Dunn J, Qiu H, Kim S, Jjingo D, Hoffman R, Kim CW, Jang I, Son D J, Kim D, Pan C, Fan Y, Jordan I K, Jo H (2014). Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis. J Clin Invest, 124(7): 3187–3199PubMedCentralPubMedGoogle Scholar
  48. 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(12): 589–596PubMedGoogle Scholar
  49. Elmasri H, Karaaslan C, Teper Y, Ghelfi E, Weng M, Ince T A, Kozakewich H, Bischoff J, Cataltepe S (2009), Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cells. FASEB J, 23: 3865–3873PubMedCentralPubMedGoogle Scholar
  50. Eriksson L, Nyström T (2014). Activation of AMP-activated protein kinase by metformin protects human coronary artery endothelial cells against diabetic lipoapoptosis. Cardiovasc Diabetol, 13(1): 152PubMedCentralPubMedGoogle Scholar
  51. Esfahanian N, Shakiba Y, Nikbin B, Soraya H, Maleki-Dizaji N, Ghazi-Khansari M, Garjani A (2012). Effect of metformin on the proliferation, migration, and MMP-2 and - 9 expression of human umbilical vein endothelial cells. Mol Med Rep, 5: 1068–1074PubMedCentralPubMedGoogle Scholar
  52. Fang L, Choi S H, Baek J S, Liu C, Almazan F, Ulrich F, Wiesner P, Taleb A, Deer E, Pattison J, Torres-Vázquez J, Li A C, Miller Y I (2013). Control of angiogenesis by AIBP-mediated cholesterol efflux. Nature, 498(7452): 118–122PubMedCentralPubMedGoogle Scholar
  53. Federici M, Menghini R, Mauriello A, Hribal M L, Ferrelli F, Lauro D, Sbraccia P, Spagnoli L G, Sesti G, Lauro R (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(4): 466–472PubMedGoogle Scholar
  54. Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B (2014). Metformin: from mechanisms of action to therapies. Cell Metab, 20(6): 953–966PubMedGoogle Scholar
  55. Forstermann U, Sessa W C (2012). Nitric oxide synthases: regulation and function. Eur Heart J, 33: 829–837, 837a–837dPubMedCentralPubMedGoogle Scholar
  56. Friedmann D R, Marmorstein R (2013). Structure and mechanism of non-histone protein acetyltransferase enzymes. FEBS J, 280: 5570–5581PubMedCentralPubMedGoogle Scholar
  57. Funk S D, Yurdagul A Jr, Orr A W (2012). Hyperglycemia and endothelial dysfunction in atherosclerosis: lessons from type 1 diabetes. Int J Vasc Med, 2012: 569654PubMedCentralPubMedGoogle Scholar
  58. Ghajar C M, Peinado H, Mori H, Matei I R, Evason K J, Brazier H, Almeida D, Koller A, Hajjar K A, Stainier D Y, Chen E I, Lyden D, Bissell M J (2013). The perivascular niche regulates breast tumour dormancy. Nat Cell Biol, 15(7): 807–817PubMedGoogle Scholar
  59. Gómez-Gaviro M V, Lovell-Badge R, Fernández-Avilés F, Lara-Pezzi E (2012). The vascular stem cell niche. J Cardiovasc Transl Res, 5(5): 618–630PubMedGoogle Scholar
  60. Gorren A C, Bec N, Schrammel A, Werner E R, Lange R, Mayer B (2000). Low-temperature optical absorption spectra suggest a redox role for tetrahydrobiopterin in both steps of nitric oxide synthase catalysis. Biochemistry, 39(38): 11763–11770PubMedGoogle Scholar
  61. Groschner L N, Waldeck-Weiermair M, Malli R, Graier W F (2012). Endothelial mitochondria-less respiration, more integration. Pflugers Arch, 464: 63–76PubMedCentralPubMedGoogle Scholar
  62. Guarani V, Deflorian G, Franco C A, Krüger M, Phng L K, Bentley K, Toussaint L, Dequiedt F, Mostoslavsky R, Schmidt M H, Zimmermann B, Brandes R P, Mione M, Westphal C H, Braun T, Zeiher A M, Gerhardt H, Dimmeler S, Potente M (2011). Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase. Nature, 473(7346): 234–238PubMedGoogle Scholar
  63. Hadad S M, Hardie D G, Appleyard V, Thompson A M (2014). Effects of metformin on breast cancer cell proliferation, the AMPK pathway and the cell cycle. Clin Transl Oncol, 16(8): 746–752PubMedGoogle Scholar
  64. Hagberg C E, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I, van Meeteren L A, Samen E, Lu L, Vanwildemeersch M, Klar J, Genove G, Pietras K, Stone-Elander S, Claesson-Welsh L, Ylä-Herttuala S, Lindahl P, Eriksson U (2010). Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature, 464(7290): 917–921PubMedGoogle Scholar
  65. Hagberg C E, Mehlem A, Falkevall A, Muhl L, Fam B C, Ortsäter H, Scotney P, Nyqvist D, Samén E, Lu L, Stone-Elander S, Proietto J, Andrikopoulos S, Sjöholm A, Nash A, Eriksson U (2012). Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature, 490(7420): 426–430PubMedGoogle Scholar
  66. Harjes U, Bridges E, McIntyre A, Fielding B A, Harris A L (2014). Fatty acid-binding protein 4, a point of convergence for angiogenic and metabolic signaling pathways in endothelial cells. J Biol Chem, 289(33): 23168–23176PubMedGoogle Scholar
  67. Hernandez-Mijares A, Rocha M, Rovira-Llopis S, Bañuls C, Bellod L, de Pablo C, Alvarez A, Roldan-Torres I, Sola-Izquierdo E, Victor V M (2013). Human leukocyte/endothelial cell interactions and mitochondrial dysfunction in type 2 diabetic patients and their association with silent myocardial ischemia. Diabetes Care, 36(6): 1695–1702PubMedCentralPubMedGoogle Scholar
  68. Hiltunen M O, Turunen M P, Häkkinen T P, Rutanen J, Hedman M, Mäkinen K, Turunen A M, Aalto-Setälä K, Ylä-Herttuala S (2002). DNA hypomethylation and methyltransferase expression in atherosclerotic lesions. Vasc Med, 7(1): 5–11PubMedGoogle Scholar
  69. Hirschhaeuser F, Sattler U G, Mueller-Klieser W (2011). Lactate: a metabolic key player in cancer. Cancer Res, 71(22): 6921–6925PubMedGoogle Scholar
  70. Hotta N, Kawamori R, Fukuda M, Shigeta Y, Aldose Reductase Inhibitor-Diabetes Complications Trial Study G (2012). Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on progression of diabetic neuropathy and other microvascular complications: multivariate epidemiological analysis based on patient background factors and severity of diabetic neuropathy. Diabet Med, 29: 1529–1533PubMedCentralPubMedGoogle Scholar
  71. Hu J, Popp R, Frömel T, Ehling M, Awwad K, Adams R H, Hammes H P, Fleming I (2014). Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19, 20-dihydroxydocosapentaenoic acid. J Exp Med, 211(2): 281–295PubMedCentralPubMedGoogle Scholar
  72. Jain R K (2013). Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol, 31(17): 2205–2218PubMedCentralPubMedGoogle Scholar
  73. Jakobsson L, Franco C A, Bentley K, Collins R T, Ponsioen B, Aspalter I M, Rosewell I, Busse M, Thurston G, Medvinsky A, Schulte-Merker S, Gerhardt H (2010). Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nat Cell Biol, 12(10): 943–953PubMedGoogle Scholar
  74. Jeon S M, Chandel N S, Hay N (2012). AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature, 485(7400): 661–665PubMedCentralPubMedGoogle Scholar
  75. Jiang Y Z, Jiménez JM, Ou K, McCormick ME, Zhang L D, Davies P F (2014). Hemodynamic disturbed flow induces differential DNA methylation of endothelial Kruppel-Like Factor 4 promoter in vitro and in vivo. Circ Res, 115(1): 32–43PubMedGoogle Scholar
  76. Kaluza D, Kroll J, Gesierich S, Yao T P, Boon R A, Hergenreider E, Tjwa M, Rössig L, Seto E, Augustin H G, Zeiher A M, Dimmeler S, Urbich C (2011). Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin. EMBO J, 30(20): 4142–4156PubMedCentralPubMedGoogle Scholar
  77. Kang D H, Lee D J, Lee KW, Park Y S, Lee J Y, Lee S H, Koh Y J, Koh G Y, Choi C, Yu D Y, Kim J, Kang S W (2011). Peroxiredoxin II is an essential antioxidant enzyme that prevents the oxidative inactivation of VEGF receptor-2 in vascular endothelial cells. Mol Cell, 44(4): 545–558PubMedGoogle Scholar
  78. Kawabe J, Hasebe N (2014). Role of the vasa vasorum and vascular resident stem cells in atherosclerosis. Biomed Res Int, 2014: 701571PubMedCentralPubMedGoogle Scholar
  79. Keunen O, Johansson M, Oudin A, Sanzey M, Rahim S A, Fack F, Thorsen F, Taxt T, Bartos M, Jirik R, Miletic H, Wang J, Stieber D, Stuhr L, Moen I, Rygh C B, Bjerkvig R, Niclou S P (2011). Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci USA, 108(9): 3749–3754PubMedCentralPubMedGoogle Scholar
  80. Kim Y R, Kim C S, Naqvi A, Kumar A, Kumar S, Hoffman T A, Irani K (2012). Epigenetic upregulation of p66shc mediates low-density lipoprotein cholesterol-induced endothelial cell dysfunction. Am J Physiol Heart Circ Physiol, 303(2): H189–H196PubMedCentralPubMedGoogle Scholar
  81. Kizhakekuttu T J, Wang J, Dharmashankar K, Ying R, Gutterman D D, Vita J A, Widlansky M E (2012). Adverse alterations in mitochondrial function contribute to type 2 diabetes mellitus-related endothelial dysfunction in humans. Arterioscler Thromb Vasc Biol, 32(10): 2531–2539PubMedCentralPubMedGoogle Scholar
  82. Kumar A, Kumar S, Vikram A, Hoffman T A, Naqvi A, Lewarchik CM, Kim Y R, Irani K (2013). Histone and DNA methylation-mediated epigenetic downregulation of endothelial Kruppel-like factor 2 by low-density lipoprotein cholesterol. Arterioscler Thromb Vasc Biol, 33(8): 1936–1942PubMedGoogle Scholar
  83. Lee J V, Carrer A, Shah S, Snyder N W, Wei S, Venneti S, Worth A J, Yuan Z F, Lim H W, Liu S, Jackson E, Aiello N M, Haas N B, Rebbeck T R, Judkins A, Won K J, Chodosh L A, Garcia B A, Stanger B Z, Feldman M D, Blair I A, Wellen K E (2014). Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab, 20(2): 306–319PubMedGoogle Scholar
  84. Lee M, Choy W C, Abid M R (2011). Direct sensing of endothelial oxidants by vascular endothelial growth factor receptor-2 and c-Src. PLoS ONE, 6(12): e28454PubMedCentralPubMedGoogle Scholar
  85. Leiper J, Nandi M (2011). The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis. Nat Rev Drug Discov, 10(4): 277–291PubMedGoogle Scholar
  86. Leopold J A, Zhang Y Y, Scribner AW, Stanton R C, Loscalzo J (2003). Glucose-6-phosphate dehydrogenase overexpression decreases endothelial cell oxidant stress and increases bioavailable nitric oxide. Arterioscler Thromb Vasc Biol, 23(3): 411–417PubMedGoogle Scholar
  87. Lim J H, Lee Y M, Chun Y S, Chen J, Kim J E, Park JW (2010). Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell, 38(6): 864–878PubMedGoogle Scholar
  88. Liu H, Yu S, Zhang H, Xu J (2012). Angiogenesis impairment in diabetes: role of methylglyoxal-induced receptor for advanced glycation endproducts, autophagy and vascular endothelial growth factor receptor 2. PLoS ONE, 7(10): e46720PubMedCentralPubMedGoogle Scholar
  89. Locasale J W (2013). Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer, 13(8): 572–583PubMedCentralPubMedGoogle Scholar
  90. Lorenzi M (2007). The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. Exp Diabetes Res, 2007: 61038PubMedCentralPubMedGoogle Scholar
  91. Lund G, Andersson L, Lauria M, Lindholm M, Fraga M F, Villar-Garea A, Ballestar E, Esteller M, Zaina S (2004). DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein E. J Biol Chem, 279(28): 29147–29154PubMedGoogle Scholar
  92. Luo B, Soesanto Y, McClain D A (2008). Protein modification by O-linked GlcNAc reduces angiogenesis by inhibiting Akt activity in endothelial cells. Arterioscler Thromb Vasc Biol, 28(4): 651–657PubMedCentralPubMedGoogle Scholar
  93. Mackenzie R M, Salt I P, Miller WH, Logan A, Ibrahim H A, Degasperi A, Dymott J A, Hamilton C A, Murphy MP, Delles C, Dominiczak A F (2013). Mitochondrial reactive oxygen species enhance AMP-activated protein kinase activation in the endothelium of patients with coronary artery disease and diabetes. Clin Sci (Lond), 124(6): 403–411Google Scholar
  94. Makino A, Scott B T, Dillmann W H (2010). Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes. Diabetologia, 53(8): 1783–1794PubMedCentralPubMedGoogle Scholar
  95. Manigrasso M B, Juranek J, Ramasamy R, Schmidt A M (2014). Unlocking the biology of RAGE in diabetic microvascular complications. Trends Endocrinol Metab, 25(1): 15–22PubMedGoogle Scholar
  96. Martin M J, Hayward R, Viros A, Marais R (2012). Metformin accelerates the growth of BRAF V600E-driven melanoma by upregulating VEGF-A. Cancer Discov, 2(4): 344–355PubMedCentralPubMedGoogle Scholar
  97. Matafome P, Sena C, Seiça R (2013). Methylglyoxal, obesity, and diabetes. Endocrine, 43(3): 472–484PubMedGoogle Scholar
  98. Meininger C J, Cai S, Parker J L, Channon K M, Kelly K A, Becker E J, Wood M K, Wade L A, Wu G (2004). GTP cyclohydrolase I gene transfer reverses tetrahydrobiopterin deficiency and increases nitric oxide synthesis in endothelial cells and isolated vessels from diabetic rats. FASEB J, 18: 1900–1902PubMedGoogle Scholar
  99. Meininger C J, Marinos R S, Hatakeyama K, Martinez-Zaguilan R, Rojas J D, Kelly K A, Wu G (2000). Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency. Biochem J, 349(Pt 1): 353–356PubMedCentralPubMedGoogle Scholar
  100. Mendelson A, Frenette P S (2014). Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med, 20(8): 833–846PubMedGoogle Scholar
  101. Merchan J R, Kovács K, Railsback J W, Kurtoglu M, Jing Y, Piña Y, Gao N, Murray T G, Lehrman M A, Lampidis T J (2010). Antiangiogenic activity of 2-deoxy-D-glucose. PLoS ONE, 5(10): e13699PubMedCentralPubMedGoogle Scholar
  102. Mishiro K, Imai T, Sugitani S, Kitashoji A, Suzuki Y, Takagi T, Chen H, Oumi Y, Tsuruma K, Shimazawa M, Hara H (2014). Diabetes mellitus aggravates hemorrhagic transformation after ischemic stroke via mitochondrial defects leading to endothelial apoptosis. PLoS ONE, 9(8): e103818PubMedCentralPubMedGoogle Scholar
  103. Mitra S, Khaidakov M, Lu J, Ayyadevara S, Szwedo J, Wang XW, Chen C, Khaidakov S, Kasula S R, Stone A, Pogribny I, Mehta J L (2011). Prior exposure to oxidized low-density lipoprotein limits apoptosis in subsequent generations of endothelial cells by altering promoter methylation. Am J Physiol Heart Circ Physiol, 301(2): H506–H513PubMedGoogle Scholar
  104. Mohammed A, Janakiram N B, Brewer M, Ritchie R L, Marya A, Lightfoot S, Steele V E, Rao C V (2013). Antidiabetic drug metformin prevents progression of pancreatic cancer by targeting in part cancer stem cells and mTOR signaling. Transl Oncol, 6(6): 649–659PubMedCentralPubMedGoogle Scholar
  105. Morgan P E, Sheahan P J, Davies M J (2014). Perturbation of human coronary artery endothelial cell redox state and NADPH generation by methylglyoxal. PLoS ONE, 9(1): e86564PubMedCentralPubMedGoogle Scholar
  106. Moschetta M, Mishima Y, Sahin I, Manier S, Glavey S, Vacca A, Roccaro A M, Ghobrial I M (2014). Role of endothelial progenitor cells in cancer progression. Biochim Biophys Acta, 1846(1): 26–39PubMedGoogle Scholar
  107. Mugoni V, Postel R, Catanzaro V, De Luca E, Turco E, Digilio G, Silengo L, Murphy M P, Medana C, Stainier D Y, Bakkers J, Santoro M M (2013). Ubiad1 is an antioxidant enzyme that regulates eNOS activity by CoQ10 synthesis. Cell, 152(3): 504–518PubMedCentralPubMedGoogle Scholar
  108. Mukutmoni-Norris M, Hubbard N E, Erickson K L (2000). Modulation of murine mammary tumor vasculature by dietary n-3 fatty acids in fish oil. Cancer Lett, 150(1): 101–109PubMedGoogle Scholar
  109. Napoli C, Martin-Padura I, de Nigris F, Giorgio M, Mansueto G, Somma P, Condorelli M, Sica G, De Rosa G, Pelicci P (2003). Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet. Proc Natl Acad Sci USA, 100(4): 2112–2116PubMedCentralPubMedGoogle Scholar
  110. Nazarenko M S, Markov A V, Lebedev I N, Sleptsov A A, Frolov A V, Barbash O L, Puzyrev V P (2013). DNA methylation profiling of the vascular tissues in the setting of atherosclerosis. Mol Biol (Mosk), 47(3): 398–404Google Scholar
  111. Nazarenko M S, Puzyrev V P, Lebedev I N, Frolov A V, Barbarash O L, Barbarash L S (2011). Methylation profiling of human atherosclerotic plaques. Mol Biol (Mosk), 45(4): 610–616Google Scholar
  112. Nef H M, Möllmann H, Joseph A, Troidl C, Voss S, Vogt A, Weber M, Hamm C W, Elsässer A (2008). Effects of 2-deoxy-D-glucose on proliferation of vascular smooth muscle cells and endothelial cells. J Int Med Res, 36(5): 986–991PubMedGoogle Scholar
  113. Nilsson E, Jansson P A, Perfilyev A, Volkov P, Pedersen M, Svensson M K, Poulsen P, Ribel-Madsen R, Pedersen N L, Almgren P, Fadista J, Rönn T, Klarlund Pedersen B, Scheele C, Vaag A, Ling C (2014). Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes. Diabetes, 63(9): 2962–2976PubMedGoogle Scholar
  114. Nishikawa T, Edelstein D, Du X L, Yamagishi S, Matsumura T, Kaneda Y, Yorek M A, Beebe D, Oates P J, Hammes H P, Giardino I, Brownlee M (2000). Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature, 404(6779): 787–790PubMedGoogle Scholar
  115. Obrosova I G, Kador P F (2011). Aldose reductase / polyol inhibitors for diabetic retinopathy. Curr Pharm Biotechnol, 12(3): 373–385PubMedGoogle Scholar
  116. Oldendorf W H, Cornford M E, Brown W J (1977). The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol, 1(5): 409–417PubMedGoogle Scholar
  117. Orecchioni S, Reggiani F, Talarico G, Mancuso P, Calleri A, Gregato G, Labanca V, Noonan D M, Dallaglio K, Albini A, Bertolini F (2014). The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells. Int J CancerGoogle Scholar
  118. Pangare M, Makino A (2012). Mitochondrial function in vascular endothelial cell in diabetes. J Smooth Muscle Res, 48(1): 1–26PubMedCentralPubMedGoogle Scholar
  119. Parra-Bonilla G, Alvarez D F, Al-Mehdi A B, Alexeyev M, Stevens T (2010). Critical role for lactate dehydrogenase A in aerobic glycolysis that sustains pulmonary microvascular endothelial cell proliferation. Am J Physiol Lung Cell Mol Physiol, 299(4): L513–L522PubMedCentralPubMedGoogle Scholar
  120. Pelosi E, Castelli G, Testa U (2014). Endothelial progenitors. Blood Cells Mol Dis, 52(4): 186–194PubMedGoogle Scholar
  121. Pernicova I, Korbonits M (2014). Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol, 10(3): 143–156PubMedGoogle Scholar
  122. Phng L K, Gerhardt H (2009). Angiogenesis: a team effort coordinated by notch. Dev Cell, 16(2): 196–208PubMedGoogle Scholar
  123. Pober J S, Min W, Bradley J R (2009). Mechanisms of endothelial dysfunction, injury, and death. Annu Rev Pathol, 4(1): 71–95PubMedGoogle Scholar
  124. Potente M, Gerhardt H, Carmeliet P (2011). Basic and therapeutic aspects of angiogenesis. Cell, 146(6): 873–887PubMedGoogle Scholar
  125. Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F, Haendeler J, Mione M, Dejana E, Alt FW, Zeiher A M, Dimmeler S (2007). SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev, 21(20): 2644–2658PubMedCentralPubMedGoogle Scholar
  126. Qu H, Yang X (2014). Metformin inhibits angiogenesis induced by interaction of hepatocellular carcinoma with hepatic stellate cells. Cell Biochem BiophysGoogle Scholar
  127. Quintero M, Colombo S L, Godfrey A, Moncada S (2006). Mitochondria as signaling organelles in the vascular endothelium. Proc Natl Acad Sci USA, 103(14): 5379–5384PubMedCentralPubMedGoogle Scholar
  128. Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G, Nishigaki I (2013). The vascular endothelium and human diseases. Int J Biol Sci, 9(10): 1057–1069PubMedCentralPubMedGoogle Scholar
  129. Rask-Madsen C, King G L (2013). Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab, 17(1): 20–33PubMedCentralPubMedGoogle Scholar
  130. Rodgers J T, Lerin C, Haas W, Gygi S P, Spiegelman B M, Puigserver P (2005). Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature, 434(7029): 113–118PubMedGoogle Scholar
  131. Rolfe B E, Worth N F, World C J, Campbell J H, Campbell G R (2005). Rho and vascular disease. Atherosclerosis, 183(1): 1–16PubMedGoogle Scholar
  132. Rose D P, Connolly J M (1999). Antiangiogenicity of docosahexaenoic acid and its role in the suppression of breast cancer cell growth in nude mice. Int J Oncol, 15(5): 1011–1015PubMedGoogle Scholar
  133. Saint-Geniez M, Jiang A, Abend S, Liu L, Sweigard H, Connor K M, Arany Z (2013). PGC-1α regulates normal and pathological angiogenesis in the retina. Am J Pathol, 182(1): 255–265PubMedCentralPubMedGoogle Scholar
  134. Santos J M, Mishra M, Kowluru R A (2014). Posttranslational modification of mitochondrial transcription factor A in impaired mitochondria biogenesis: implications in diabetic retinopathy and metabolic memory phenomenon. Exp Eye Res, 121: 168–177PubMedCentralPubMedGoogle Scholar
  135. Sawada N, Jiang A, Takizawa F, Safdar A, Manika A, Tesmenitsky Y, Kang K T, Bischoff J, Kalwa H, Sartoretto J L, Kamei Y, Benjamin L E, Watada H, Ogawa Y, Higashikuni Y, Kessinger C W, Jaffer F A, Michel T, Sata M, Croce K, Tanaka R, Arany Z (2014). Endothelial PGC-1α mediates vascular dysfunction in diabetes. Cell Metab, 19(2): 246–258PubMedCentralPubMedGoogle Scholar
  136. Schoors S, Cantelmo A R, Georgiadou M, Stapor P, Wang X, Quaegebeur A, Cauwenberghs S, Wong B W, Bifari F, Decimo I, Schoonjans L, De Bock K, Dewerchin M, Carmeliet P (2014a). Incomplete and transitory decrease of glycolysis: a new paradigm for anti-angiogenic therapy? Cell Cycle, 13(1): 16–22PubMedCentralPubMedGoogle Scholar
  137. Schoors S, De Bock K, Cantelmo A R, Georgiadou M, Ghesquière B, Cauwenberghs S, Kuchnio A, Wong B W, Quaegebeur A, Goveia J, Bifari F, Wang X, Blanco R, Tembuyser B, Cornelissen I, Bouché A, Vinckier S, Diaz-Moralli S, Gerhardt H, Telang S, Cascante M, Chesney J, Dewerchin M, Carmeliet P (2014b). Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell Metab, 19(1): 37–48PubMedGoogle Scholar
  138. Sena C M, Matafome P, Louro T, Nunes E, Fernandes R, Seiça R M (2011). Metformin restores endothelial function in aorta of diabetic rats. Br J Pharmacol, 163(2): 424–437PubMedCentralPubMedGoogle Scholar
  139. Sena C M, Pereira A M, Seiça R (2013). Endothelial dysfunction- a major mediator of diabetic vascular disease. Biochim Biophys Acta, 1832(12): 2216–2231PubMedGoogle Scholar
  140. Singh M, Ferrara N (2012). Modeling and predicting clinical efficacy for drugs targeting the tumor milieu. Nat Biotechnol, 30(7): 648–657PubMedGoogle Scholar
  141. Sonveaux P, Copetti T, De Saedeleer C J, Végran F, Verrax J, Kennedy K M, Moon E J, Dhup S, Danhier P, Frérart F, Gallez B, Ribeiro A, Michiels C, Dewhirst M W, Feron O (2012). Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS ONE, 7(3): e33418PubMedCentralPubMedGoogle Scholar
  142. Sounni N E, Cimino J, Blacher S, Primac I, Truong A, Mazzucchelli G, Paye A, Calligaris D, Debois D, De Tullio P, Mari B, De Pauw E, Noel A (2014). Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metab, 20(2): 280–294PubMedGoogle Scholar
  143. Stefan M, Zhang W, Concepcion E, Yi Z, Tomer Y (2014). DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology. J Autoimmun, 50: 33–37PubMedGoogle Scholar
  144. Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Lüscher T, Rabelink T (1997). Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest, 99(1): 41–46PubMedCentralPubMedGoogle Scholar
  145. Struck A W, Thompson M L, Wong L S, Micklefield J (2012). Sadenosyl-methionine-dependent methyltransferases: highly versatile enzymes in biocatalysis, biosynthesis and other biotechnological applications. ChemBioChem, 13(18): 2642–2655PubMedGoogle Scholar
  146. Su Y, Qadri S M, Wu L, Liu L (2013). Methylglyoxal modulates endothelial nitric oxide synthase-associated functions in EA.hy926 endothelial cells. Cardiovasc Diabetol, 12(1): 134PubMedCentralPubMedGoogle Scholar
  147. Sudhahar V, Urao N, Oshikawa J, McKinney R D, Llanos RM, Mercer J F, Ushio-Fukai M, Fukai T (2013). Copper transporter ATP7A protects against endothelial dysfunction in type 1 diabetic mice by regulating extracellular superoxide dismutase. Diabetes, 62(11): 3839–3850PubMedCentralPubMedGoogle Scholar
  148. Sutendra G, Kinnaird A, Dromparis P, Paulin R, Stenson T H, Haromy A, Hashimoto K, Zhang N, Flaim E, Michelakis E D (2014). A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation. Cell, 158(1): 84–97PubMedGoogle Scholar
  149. Tabe Y, Konopleva M (2014). Advances in understanding the leukaemia microenvironment. Br J Haematol, 164(6): 767–778PubMedCentralPubMedGoogle Scholar
  150. Takahashi N, Shibata R, Ouchi N, Sugimoto M, Murohara T, Komori K (2014). Metformin stimulates ischemia-induced revascularization through an eNOS dependent pathway in the ischemic hindlimb mice model. J Vasc SurgGoogle Scholar
  151. Takahashi T, Shibuya M (1997). The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts. Oncogene, 14(17): 2079–2089PubMedGoogle Scholar
  152. Takakura N (2012). Formation and regulation of the cancer stem cell niche. Cancer Sci, 103(7): 1177–1181PubMedGoogle Scholar
  153. Takaya T, Hirata K, Yamashita T, Shinohara M, Sasaki N, Inoue N, Yada T, Goto M, Fukatsu A, Hayashi T, Alp N J, Channon K M, Yokoyama M, Kawashima S (2007). A specific role for eNOS-derived reactive oxygen species in atherosclerosis progression. Arterioscler Thromb Vasc Biol, 27(7): 1632–1637PubMedGoogle Scholar
  154. Tan B K, Adya R, Chen J, Farhatullah S, Heutling D, Mitchell D, Lehnert H, Randeva H S (2009). Metformin decreases angiogenesis via NF-kappaB and Erk1/2/Erk5 pathways by increasing the antiangiogenic thrombospondin-1. Cardiovasc Res, 83(3): 566–574PubMedGoogle Scholar
  155. Tang X, Luo Y X, Chen H Z, Liu D P (2014). Mitochondria, endothelial cell function, and vascular diseases. Front Physiol, 5: 175PubMedCentralPubMedGoogle Scholar
  156. Tevar R, Jho D H, Babcock T, Helton W S, Espat N J (2002). Omega-3 fatty acid supplementation reduces tumor growth and vascular endothelial growth factor expression in a model of progressive nonmetastasizing malignancy. JPEN J Parenter Enteral Nutr, 26(5): 285–289PubMedGoogle Scholar
  157. Tian X Y, Wong W T, Xu A, Lu Y, Zhang Y, Wang L, Cheang W S, Wang Y, Yao X, Huang Y (2012). Uncoupling protein-2 protects endothelial function in diet-induced obese mice. Circ Res, 110(9): 1211–1216PubMedGoogle Scholar
  158. Tousoulis D, Kampoli A M, Tentolouris C, Papageorgiou N, Stefanadis C (2012). The role of nitric oxide on endothelial function. Curr Vasc Pharmacol, 10(1): 4–18PubMedGoogle Scholar
  159. Tsuji M, Murota S I, Morita I (2003). Docosapentaenoic acid (22:5, n-3) suppressed tube-forming activity in endothelial cells induced by vascular endothelial growth factor. Prostaglandins Leukot Essent Fatty Acids, 68(5): 337–342PubMedGoogle Scholar
  160. Tsuzuki T, Shibata A, Kawakami Y, Nakagawa K, Miyazawa T (2007). Conjugated eicosapentaenoic acid inhibits vascular endothelial growth factor-induced angiogenesis by suppressing the migration of human umbilical vein endothelial cells. J Nutr, 137(3): 641–646PubMedGoogle Scholar
  161. Unterluggauer H, Mazurek S, Lener B, Hütter E, Eigenbrodt E, Zwerschke W, Jansen-Dürr P (2008). Premature senescence of human endothelial cells induced by inhibition of glutaminase. Biogerontology, 9(4): 247–259PubMedGoogle Scholar
  162. Valente A J, Irimpen AM, Siebenlist U, Chandrasekar B (2014). OxLDL induces endothelial dysfunction and death via TRAF3IP2: inhibition by HDL3 and AMPK activators. Free Radic Biol Med, 70: 117–128PubMedGoogle Scholar
  163. van Beijnum J R, Dings R P, van der Linden E, Zwaans BM, Ramaekers F C, Mayo K H, Griffioen A W (2006). Gene expression of tumor angiogenesis dissected: specific targeting of colon cancer angiogenic vasculature. Blood, 108(7): 2339–2348PubMedGoogle Scholar
  164. van Eupen M G, Schram M T, Colhoun H M, Hanssen N M, Niessen H W, Tarnow L, Parving H H, Rossing P, Stehouwer C D, Schalkwijk C G (2013). The methylglyoxal-derived AGE tetrahydropyrimidine is increased in plasma of individuals with type 1 diabetes mellitus and in atherosclerotic lesions and is associated with sVCAM-1. Diabetologia, 56(8): 1845–1855PubMedGoogle Scholar
  165. Végran 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(7): 2550–2560PubMedGoogle Scholar
  166. Venkatesan B, Valente A J, Das N A, Carpenter A J, Yoshida T, Delafontaine J L, Siebenlist U, Chandrasekar B (2013). CIKS (Act1 or TRAF3IP2) mediates high glucose-induced endothelial dysfunction. Cell Signal, 25(1): 359–371PubMedCentralPubMedGoogle Scholar
  167. Venna V R, Li J, Hammond MD, Mancini N S, McCullough L D (2014). Chronic metformin treatment improves post-stroke angiogenesis and recovery after experimental stroke. Eur J Neurosci, 39(12): 2129–2138PubMedGoogle Scholar
  168. Vizán P, Sánchez-Tena S, Alcarraz-Vizán G, Soler M, Messeguer R, Pujol M D, Lee W N, Cascante M (2009). Characterization of the metabolic changes underlying growth factor angiogenic activation: identification of new potential therapeutic targets. Carcinogenesis, 30(6): 946–952PubMedGoogle Scholar
  169. Wang W, Zhu J, Lyu F, Panigrahy D, Ferrara K W, Hammock B, Zhang G (2014). ω-3 polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer. Prostaglandins Other Lipid Mediat, 113–115: 13–20PubMedGoogle Scholar
  170. Warren C M, Ziyad S, Briot A, Der A, Iruela-Arispe M L (2014). A ligand-independent VEGFR2 signaling pathway limits angiogenic responses in diabetes. Sci Signal, 7(307): ra1PubMedCentralPubMedGoogle Scholar
  171. Wautier J L, Schmidt A M (2004). Protein glycation: a firm link to endothelial cell dysfunction. Circ Res, 95(3): 233–238PubMedGoogle Scholar
  172. Wei X, Schneider J G, Shenouda SM, Lee A, Towler D A, Chakravarthy M V, Vita J A, Semenkovich C F (2011). De novo lipogenesis maintains vascular homeostasis through endothelial nitric-oxide synthase (eNOS) palmitoylation. J Biol Chem, 286(4): 2933–2945PubMedCentralPubMedGoogle Scholar
  173. Wellen K E, Hatzivassiliou G, Sachdeva U M, Bui T V, Cross J R, Thompson C B (2009). ATP-citrate lyase links cellular metabolism to histone acetylation. Science, 324(5930): 1076–1080PubMedCentralPubMedGoogle Scholar
  174. Wilkinson M J, Laffin L J, Davidson M H (2014). Overcoming toxicity and side-effects of lipid-lowering therapies. Best Pract Res Clin Endocrinol Metab, 28(3): 439–452PubMedGoogle Scholar
  175. Wu G, Haynes T E, Li H, Meininger C J (2000). Glutamine metabolism in endothelial cells: ornithine synthesis from glutamine via pyrroline-5-carboxylate synthase. Comp Biochem Physiol A Mol Integr Physiol, 126(1): 115–123PubMedGoogle Scholar
  176. Wu G, Meininger C J (1995). Impaired arginine metabolism and NO synthesis in coronary endothelial cells of the spontaneously diabetic BB rat. Am J Physiol, 269(4 Pt 2): H1312–H1318PubMedGoogle Scholar
  177. Xu Y, An X, Guo X, Habtetsion T G, Wang Y, Xu X, Kandala S, Li Q, Li H, Zhang C, Caldwell R B, Fulton D J, Su Y, Hoda MN, Zhou G, Wu C, Huo Y (2014). Endothelial PFKFB3 plays a critical role in angiogenesis. Arterioscler Thromb Vasc Biol, 34(6): 1231–1239PubMedGoogle Scholar
  178. Yanai R, Mulki L, Hasegawa E, Takeuchi K, Sweigard H, Suzuki J, Gaissert P, Vavvas D G, Sonoda K H, Rothe M, Schunck WH, Miller J W, Connor K M (2014). Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization. Proc Natl Acad Sci USA, 111(26): 9603–9608PubMedCentralPubMedGoogle Scholar
  179. Yang B T, Dayeh T A, Volkov P A, Kirkpatrick C L, Malmgren S, Jing X, Renström E, Wollheim C B, Nitert M D, Ling C (2012). Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes. Mol Endocrinol, 26(7): 1203–1212PubMedGoogle Scholar
  180. Yang S P, Morita I, Murota S I (1998). Eicosapentaenoic acid attenuates vascular endothelial growth factor-induced proliferation via inhibiting Flk-1 receptor expression in bovine carotid artery endothelial cells. J Cell Physiol, 176(2): 342–349PubMedGoogle Scholar
  181. Yeh W L, Lin C J, Fu W M (2008). Enhancement of glucose transporter expression of brain endothelial cells by vascular endothelial growth factor derived from glioma exposed to hypoxia. Mol Pharmacol, 73(1): 170–177PubMedGoogle Scholar
  182. Zecchin A, Pattarini L, Gutierrez MI, Mano M, Mai A, Valente S, Myers M P, Pantano S, Giacca M (2014). Reversible acetylation regulates vascular endothelial growth factor receptor-2 activity. J Mol Cell Biol, 6(2): 116–127PubMedGoogle Scholar
  183. Zhang D, Li J, Wang F, Hu J, Wang S, Sun Y (2014). 2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy. Cancer Lett, 355(2): 176–183PubMedGoogle Scholar
  184. Zhang G, Panigrahy D, Mahakian L M, Yang J, Liu J Y, Stephen Lee K S, Wettersten H I, Ulu A, Hu X, Tam S, Hwang S H, Ingham E S, Kieran MW, Weiss R H, Ferrara KW, Hammock B D (2013). Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis. Proc Natl Acad Sci USA, 110(16): 6530–6535PubMedCentralPubMedGoogle Scholar
  185. Zhang Z, Apse K, Pang J, Stanton R C (2000). High glucose inhibits glucose-6-phosphate dehydrogenase via cAMP in aortic endothelial cells. J Biol Chem, 275(51): 40042–40047PubMedGoogle Scholar
  186. Zou M H, Shi C, Cohen R A (2002). Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest, 109(6): 817–826PubMedCentralPubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Annalisa Zecchin
    • 1
    • 2
  • Aleksandra Brajic
    • 1
    • 2
  • Peter Carmeliet
    • 1
    • 2
    Email author
  1. 1.Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research CenterVIBLeuvenBelgium
  2. 2.Laboratory of Angiogenesis and Neurovascular Link, Department of OncologyKU LeuvenLeuvenBelgium

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