Targeting endothelial cell metabolism: new therapeutic prospects?

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.

Key words： angiogenesis; metabolism; endothelial cell dysfunction; anti-angiogenic therapy

Acknowledgments

We apologize for not being able to cite the work of all other studies related to this topic because of space restrictions. The authors gratefully acknowledge Guy Eelen, Jermaine Goveia and Brian Wong for valuable comments. A.B. is PhD student supported by an Erasmus Mundus Western Balkans (ERAWEB) scholarship. The work of P.C. is supported by a Federal Government Belgium grant (IUAP P7/03), long-term structural Methusalem funding by the Flemish Government, the Research Foundation Flanders (FWO), the Foundation Leducq Transatlantic Network (ARTEMIS), Foundation against cancer, an European Research Council (ERC) Advanced Research Grant (EU-ERC269073) and the AXA Research Fund.

Compliance with ethics <?Pub Caret?>guidelines

Peter Carmeliet is named as an inventor on patent application regarding subject matter related to the findings reviewed in this publication. Annalisa Zecchin and Aleksandra Brajic declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review boards or ethics committees.

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): 2823–2832

PMID

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): 1174–1182

PMID

3 Antonetti D A, Klein R, Gardner T W (2012). Diabetic retinopathy. N Engl J Med, 366(13): 1227–1239

PMID

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): 335–345

PMID

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 B M (2008). HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature, 451(7181): 1008–1012

PMID

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): 523–535

PMID

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): 967–973

PMID

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): 156–164

PMID

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): 115–121

PMID

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): 1124–1135

PMID

11 Biasucci L M, Biasillo G, Stefanelli A (2010). Inflammatory markers, cholesterol and statins: pathophysiological role and clinical importance. Clin Chem Lab Med, 48: 1685–1691

12 Bode-Böger S M, Scalera F, Ignarro L J (2007). The L-arginine paradox: Importance of the L-arginine/asymmetrical dimethylarginine ratio. Pharmacol Ther, 114(3): 295–306

PMID

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: 447

14 Brandes R P, Weissmann N, Schröder K (2014). Redox-mediated signal transduction by cardiovascular Nox NADPH oxidases. J Mol Cell Cardiol, 73: 70–79

PMID

15 Browne C D, Hindmarsh E J, Smith J W (2006). Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor. FASEB J, 20: 2027–2035

16 Brownlee M (2001). Biochemistry and molecular cell biology of diabetic complications. Nature, 414(6865): 813–820

PMID

17 Brownlee M (2005). The pathobiology of diabetic complications: a unifying mechanism. Diabetes, 54(6): 1615–1625

PMID

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): 823–831

PMID

19 Calder P C (2014). Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochim Biophys Acta

PMID

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): 2303–2310

PMID

21 Carracedo A, Cantley L C, Pandolfi P P (2013). Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer, 13(4): 227–232

PMID

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): 691–700

PMID

23 Chan J R, Böger R H, Bode-Böger S M, 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): 1040–1046

PMID

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–C1040

PMID

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): 536–550

PMID

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): 239–245

PMID

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): 944–953

PMID

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): 868–873

PMID

29 Coutelle O, Hornig-Do H T, Witt A, Andree M, Schiffmann L M, Piekarek M, Brinkmann K, Seeger J M, 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): 624–639

PMID

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): 1136–1144

PMID

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): 744–758

PMID

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): 120–133

PMID

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): 1276–1282

PMID

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): 1055–1066

PMID

35 Davignon J, Ganz P (2004). Role of endothelial dysfunction in atherosclerosis. Circulation, 109(23 Suppl 1): III27–III32

PMID

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): 496–505

PMID

37 Dawson M A, Kouzarides T (2012). Cancer epigenetics: from mechanism to therapy. Cell, 150(1): 12–27

PMID

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): e1004160

PMID

39 De Bock K, Georgiadou M, Carmeliet P (2013a). Role of endothelial cell metabolism in vessel sprouting. Cell Metab, 18(5): 634–647

PMID

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): 651–663

PMID

41 Dhillon B, Badiwala M V, Maitland A, Rao V, Li S H, Verma S (2003). Tetrahydrobiopterin attenuates homocysteine induced endothelial dysfunction. Mol Cell Biochem, 247(1-2): 223–227

PMID

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): 137–145

PMID

43 Dowling R J O, Niraula S, Stambolic V, Goodwin P J (2012). Metformin in cancer: translational challenges. J Mol Endocrinol, 48(3): R31–R43

PMID

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): 1049–1057

PMID

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): 1341–1348

PMID

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): 12222–12226

PMID

47 Dunn J, Qiu H, Kim S, Jjingo D, Hoffman R, Kim C W, 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): 3187–3199

PMID

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): 589–596

PMID

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: 3865–3873

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): 152

PMID

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: 1068–1074

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): 118–122

PMID

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): 466–472

PMID

54 Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B (2014). Metformin: from mechanisms of action to therapies. Cell Metab, 20(6): 953–966

PMID

55 Forstermann U, Sessa W C (2012). Nitric oxide synthases: regulation and function. Eur Heart J, 33: 829–837, 837a–837d

56 Friedmann D R, Marmorstein R (2013). Structure and mechanism of non-histone protein acetyltransferase enzymes. FEBS J, 280: 5570–5581

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: 569654

PMID

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): 807–817

PMID

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): 618–630

PMID

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): 11763–11770

PMID

61 Groschner L N, Waldeck-Weiermair M, Malli R, Graier W F (2012). Endothelial mitochondria–less respiration, more integration. Pflugers Arch, 464: 63–76

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): 234–238

PMID

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): 746–752

PMID

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): 917–921

PMID

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): 426–430

PMID

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): 23168–23176

PMID

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): 1695–1702

PMID

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): 5–11

PMID

69 Hirschhaeuser F, Sattler U G, Mueller-Klieser W (2011). Lactate: a metabolic key player in cancer. Cancer Res, 71(22): 6921–6925

PMID

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: 1529–1533

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): 281–295

PMID

72 Jain R K (2013). Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol, 31(17): 2205–2218

PMID

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): 943–953

PMID

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): 661–665

PMID

75 Jiang Y Z, Jiménez J M, Ou K, McCormick M E, 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): 32–43

PMID

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): 4142–4156

PMID

77 Kang D H, Lee D J, Lee K W, 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): 545–558

PMID

78 Kawabe J, Hasebe N (2014). Role of the vasa vasorum and vascular resident stem cells in atherosclerosis. Biomed Res Int, 2014: 701571

PMID

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): 3749–3754

PMID

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–H196

PMID

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): 2531–2539

PMID

82 Kumar A, Kumar S, Vikram A, Hoffman T A, Naqvi A, Lewarchik C M, 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): 1936–1942

PMID

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): 306–319

PMID

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): e28454

PMID

85 Leiper J, Nandi M (2011). The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis. Nat Rev Drug Discov, 10(4): 277–291

PMID

86 Leopold J A, Zhang Y Y, Scribner A W, 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): 411–417

PMID

87 Lim J H, Lee Y M, Chun Y S, Chen J, Kim J E, Park J W (2010). Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell, 38(6): 864–878

PMID

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): e46720

PMID

89 Locasale J W (2013). Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer, 13(8): 572–583

PMID

90 Lorenzi M (2007). The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. Exp Diabetes Res, 2007: 61038

PMID

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): 29147–29154

PMID

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): 651–657

PMID

93 Mackenzie R M, Salt I P, Miller W H, Logan A, Ibrahim H A, Degasperi A, Dymott J A, Hamilton C A, Murphy M P, 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): 403–411

PMID

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): 1783–1794

PMID

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): 15–22

PMID

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): 344–355

PMID

97 Matafome P, Sena C, Seiça R (2013). Methylglyoxal, obesity, and diabetes. Endocrine, 43(3): 472–484

PMID

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: 1900–1902

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): 353–356

PMID

100 Mendelson A, Frenette P S (2014). Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med, 20(8): 833–846

PMID

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): e13699

PMID

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): e103818

PMID

103 Mitra S, Khaidakov M, Lu J, Ayyadevara S, Szwedo J, Wang X W, 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–H513

PMID

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): 649–659

PMID

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): e86564

PMID

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): 26–39

PMID

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): 504–518

PMID

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): 101–109

PMID

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): 2112–2116

PMID

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): 398–404

PMID

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): 610–616

PMID

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): 986–991

PMID

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): 2962–2976

PMID

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): 787–790

PMID

115 Obrosova I G, Kador P F (2011). Aldose reductase / polyol inhibitors for diabetic retinopathy. Curr Pharm Biotechnol, 12(3): 373–385

PMID

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): 409–417

PMID

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 Cancer

PMID

118 Pangare M, Makino A (2012). Mitochondrial function in vascular endothelial cell in diabetes. J Smooth Muscle Res, 48(1): 1–26

PMID

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–L522

PMID

120 Pelosi E, Castelli G, Testa U (2014). Endothelial progenitors. Blood Cells Mol Dis, 52(4): 186–194

PMID

121 Pernicova I, Korbonits M (2014). Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol, 10(3): 143–156

PMID

122 Phng L K, Gerhardt H (2009). Angiogenesis: a team effort coordinated by notch. Dev Cell, 16(2): 196–208

PMID

123 Pober J S, Min W, Bradley J R (2009). Mechanisms of endothelial dysfunction, injury, and death. Annu Rev Pathol, 4(1): 71–95

PMID

124 Potente M, Gerhardt H, Carmeliet P (2011). Basic and therapeutic aspects of angiogenesis. Cell, 146(6): 873–887

PMID

125 Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F, Haendeler J, Mione M, Dejana E, Alt F W, Zeiher A M, Dimmeler S (2007). SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev, 21(20): 2644–2658

PMID

126 Qu H, Yang X (2014). Metformin inhibits angiogenesis induced by interaction of hepatocellular carcinoma with hepatic stellate cells. Cell Biochem Biophys

PMID

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): 5379–5384

PMID

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): 1057–1069

PMID

129 Rask-Madsen C, King G L (2013). Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab, 17(1): 20–33

PMID

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): 113–118

PMID

131 Rolfe B E, Worth N F, World C J, Campbell J H, Campbell G R (2005). Rho and vascular disease. Atherosclerosis, 183(1): 1–16

PMID

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): 1011–1015

PMID

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): 255–265

PMID

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: 168–177

PMID

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): 246–258

PMID

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): 16–22

PMID

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): 37–48

PMID

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): 424–437

PMID

139 Sena C M, Pereira A M, Seiça R (2013). Endothelial dysfunction- a major mediator of diabetic vascular disease. Biochim Biophys Acta, 1832(12): 2216–2231

PMID

140 Singh M, Ferrara N (2012). Modeling and predicting clinical efficacy for drugs targeting the tumor milieu. Nat Biotechnol, 30(7): 648–657

PMID

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): e33418

PMID

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): 280–294

PMID

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: 33–37

PMID

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): 41–46

PMID

145 Struck A W, Thompson M L, Wong L S, Micklefield J (2012). S-adenosyl-methionine-dependent methyltransferases: highly versatile enzymes in biocatalysis, biosynthesis and other biotechnological applications. ChemBioChem, 13(18): 2642–2655

PMID

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): 134

PMID

147 Sudhahar V, Urao N, Oshikawa J, McKinney R D, Llanos R M, 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): 3839–3850

PMID

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): 84–97

PMID

149 Tabe Y, Konopleva M (2014). Advances in understanding the leukaemia microenvironment. Br J Haematol, 164(6): 767–778

PMID

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 Surg

PMID

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): 2079–2089

PMID

152 Takakura N (2012). Formation and regulation of the cancer stem cell niche. Cancer Sci, 103(7): 1177–1181

PMID

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): 1632–1637

PMID

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): 566–574

PMID

155 Tang X, Luo Y X, Chen H Z, Liu D P (2014). Mitochondria, endothelial cell function, and vascular diseases. Front Physiol, 5: 175

PMID

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 non-metastasizing malignancy. JPEN J Parenter Enteral Nutr, 26(5): 285–289

PMID

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): 1211–1216

PMID

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): 4–18

PMID

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): 337–342

PMID

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): 641–646

PMID

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): 247–259

PMID

162 Valente A J, Irimpen A M, Siebenlist U, Chandrasekar B (2014). OxLDL induces endothelial dysfunction and death via TRAF3IP2: inhibition by HDL3 and AMPK activators. Free Radic Biol Med, 70: 117–128

PMID

163 van Beijnum J R, Dings R P, van der Linden E, Zwaans B M, 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): 2339–2348

PMID

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): 1845–1855

PMID

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): 2550–2560

PMID

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): 359–371

PMID

167 Venna V R, Li J, Hammond M D, Mancini N S, McCullough L D (2014). Chronic metformin treatment improves post-stroke angiogenesis and recovery after experimental stroke. Eur J Neurosci, 39(12): 2129–2138

PMID

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): 946–952

PMID

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: 13–20

PMID

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): ra1

PMID

171 Wautier J L, Schmidt A M (2004). Protein glycation: a firm link to endothelial cell dysfunction. Circ Res, 95(3): 233–238

PMID

172 Wei X, Schneider J G, Shenouda S M, 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): 2933–2945

PMID

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): 1076–1080

PMID

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): 439–452

PMID

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): 115–123

PMID

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–H1318

PMID

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 M N, Zhou G, Wu C, Huo Y (2014). Endothelial PFKFB3 plays a critical role in angiogenesis. Arterioscler Thromb Vasc Biol, 34(6): 1231–1239

PMID

178 Yanai R, Mulki L, Hasegawa E, Takeuchi K, Sweigard H, Suzuki J, Gaissert P, Vavvas D G, Sonoda K H, Rothe M, Schunck W H, 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): 9603–9608

PMID

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): 1203–1212

PMID

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): 342–349

PMID

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): 170–177

PMID

182 Zecchin A, Pattarini L, Gutierrez M I, 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): 116–127

PMID

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): 176–183

PMID

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 M W, Weiss R H, Ferrara K W, Hammock B D (2013). Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis. Proc Natl Acad Sci USA, 110(16): 6530–6535

PMID

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): 40042–40047

PMID

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): 817–826

PMID