Cellular and Molecular Life Sciences

, Volume 69, Issue 7, pp 1049–1065 | Cite as

MicroRNAs mediate metabolic stresses and angiogenesis

  • Francesca PatellaEmail author
  • Giuseppe Rainaldi


MicroRNAs are short endogenous RNA molecules that are able to regulate (mainly inhibiting) gene expression at the post-transcriptional level. The MicroRNA expression profile is cell-specific, but it is sensitive to perturbations produced by stresses and diseases. Endothelial cells subjected to metabolic stresses, such as calorie restriction, nutrients excess (glucose, cholesterol, lipids) and hypoxia may alter their functionality. This is predictive for the development of pathologies like atherosclerosis, diabetes, and hypertension. Moreover, cancer cells can activate a resting endothelium by secreting pro-angiogenic factors, in order to promote neoangiogenesis, which is essential for tumor growth. Endothelial altered phenotype is mirrored by altered mRNA, microRNA, and protein expression, with a microRNA being able to control pathways by regulating the expression of multiple mRNAs. In this review we will consider the involvement of microRNAs in modulating the response of endothelial cells to metabolic stresses and their role in promoting or halting angiogenesis.


Endothelial cells Angiogenesis MicroRNAs Metabolic stresses Metabolic disorders Cancer 



Endothelial cells


Vascular endothelial growth factor


Basic fibroblast growth factor


Reactive oxygen species


Nitric oxide


Endothelial nitric oxide synthase


Transcription factors



This work was supported by Associazione Italiana per la Ricerca sul Cancro, AIRC (Project number 4753) and by Istituto Superiore di Sanità, ISS (Project number 527/A/3A/4). We thank Mrs. Penelope Ivall Garrud for careful reading of the manuscript and Serena Lucotti for drawing most of the figures.


  1. 1.
    He L, Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5(7):522–531PubMedCrossRefGoogle Scholar
  2. 2.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297PubMedCrossRefGoogle Scholar
  3. 3.
    Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9(2):102–114. doi: 10.1038/nrg2290 PubMedCrossRefGoogle Scholar
  4. 4.
    Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433(7027):769–773PubMedCrossRefGoogle Scholar
  5. 5.
    Orom UA, Lund AH (2010) Experimental identification of microRNA targets. Gene 451(1–2):1–5. pii: S0378-1119(09)00577-0PubMedCrossRefGoogle Scholar
  6. 6.
    Vinther J, Hedegaard MM, Gardner PP, Andersen JS, Arctander P (2006) Identification of miRNA targets with stable isotope labeling by amino acids in cell culture. Nucleic Acids Res 34(16):e107PubMedCrossRefGoogle Scholar
  7. 7.
    Karginov FV, Conaco C, Xuan Z, Schmidt BH, Parker JS, Mandel G, Hannon GJ (2007) A biochemical approach to identifying microRNA targets. Proc Natl Acad Sci USA 104(49):19291–19296PubMedCrossRefGoogle Scholar
  8. 8.
    Orom UA, Lund AH (2007) Isolation of microRNA targets using biotinylated synthetic microRNAs. Methods San Diego Calif 43(2):162–165. pii: S1046-2023(07)00097-7Google Scholar
  9. 9.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435(7043):834–838PubMedCrossRefGoogle Scholar
  10. 10.
    Gallagher IJ, Scheele C, Keller P, Nielsen AR, Remenyi J, Fischer CP, Roder K, Babraj J, Wahlestedt C, Hutvagner G, Pedersen BK, Timmons JA (2010) Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes. Genome Med 2(2):9. doi: 10.1186/gm130 PubMedCrossRefGoogle Scholar
  11. 11.
    Pitto L, Ripoli A, Cremisi F, Simili M, Rainaldi G (2008) microRNA(interference) networks are embedded in the gene regulatory networks. Cell cycle Georgetown Tex 7(16):2458–2461 6455CrossRefGoogle Scholar
  12. 12.
    Tuccoli A, Poliseno L, Rainaldi G (2006) miRNAs regulate miRNAs: coordinated transcriptional and post-transcriptional regulation. Cell cycle (Georgetown. Tex) 5(21):2473–2476CrossRefGoogle Scholar
  13. 13.
    Zhou Y, Ferguson J, Chang JT, Kluger Y (2007) Inter- and intra-combinatorial regulation by transcription factors and microRNAs. BMC Genom 8:396CrossRefGoogle Scholar
  14. 14.
    Chen CY, Chen ST, Fuh CS, Juan HF, Huang HC (2011) Coregulation of transcription factors and microRNAs in human transcriptional regulatory network. BMC Bioinform 12(Suppl 1):41. doi: 10.1186/1471-2105-12-S1-S41 CrossRefGoogle Scholar
  15. 15.
    Tsang J, Zhu J, van Oudenaarden A (2007) MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. Mol Cell 26(5):753–767PubMedCrossRefGoogle Scholar
  16. 16.
    Coller HA, Forman JJ, Legesse-Miller A (2007) “Myc’ed messages”: myc induces transcription of E2F1 while inhibiting its translation via a microRNA polycistron. PLoS Genet 3(8):e146PubMedCrossRefGoogle Scholar
  17. 17.
    Rizzo M, Mariani L, Pitto L, Rainaldi G, Simili M (2010) miR-20a and miR-290, multi-faceted players with a role in tumourigenesis and senescence. J Cell Mol Med 14(11):2633–2640. doi: 10.1111/j.1582-4934.2010.01173.x PubMedCrossRefGoogle Scholar
  18. 18.
    Hua Z, Lv Q, Ye W, Wong CK, Cai G, Gu D, Ji Y, Zhao C, Wang J, Yang BB, Zhang Y (2006) MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia. PLoS ONE 1:e116PubMedCrossRefGoogle Scholar
  19. 19.
    Marasa BS, Srikantan S, Masuda K, Abdelmohsen K, Kuwano Y, Yang X, Martindale JL, Rinker-Schaeffer CW, Gorospe M (2009) Increased MKK4 abundance with replicative senescence is linked to the joint reduction of multiple microRNAs. Sci Signal 2(94):ra69. pii:2/94/ra69PubMedCrossRefGoogle Scholar
  20. 20.
    Mavrakis KJ, Van Der Meulen J, Wolfe AL, Liu X, Mets E, Taghon T, Khan AA, Setti M, Rondou P, Vandenberghe P, Delabesse E, Benoit Y, Socci NB, Leslie CS, Van Vlierberghe P, Speleman F, Wendel HG (2011) A cooperative microRNA-tumor suppressor gene network in acute T cell lymphoblastic leukemia (T-ALL). Nat Genet. doi: 10.1038/ng.858
  21. 21.
    Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, Barnathan ES, McCrae KR, Hug BA, Schmidt AM, Stern DM (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91(10):3527–3561PubMedGoogle Scholar
  22. 22.
    Sumpio BE, Riley JT, Dardik A (2002) Cells in focus: endothelial cell. Int J Biochem Cell Biol 34(12):1508–1512. pii:S1357272502000754PubMedCrossRefGoogle Scholar
  23. 23.
    Hobson B, Denekamp J (1984) Endothelial proliferation in tumours and normal tissues: continuous labelling studies. Br J Cancer 49(4):405–413PubMedCrossRefGoogle Scholar
  24. 24.
    Tabit CE, Chung WB, Hamburg NM, Vita JA (2010) Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications. Rev Endocr Metab Disord 11(1):61–74. doi: 10.1007/s11154-010-9134-4 PubMedCrossRefGoogle Scholar
  25. 25.
    Yang Z, Ming XF (2006) Recent advances in understanding endothelial dysfunction in atherosclerosis. Clin Med Res 4(1):53–65PubMedCrossRefGoogle Scholar
  26. 26.
    Esper RJ, Nordaby RA, Vilarino JO, Paragano A, Cacharron JL, Machado RA (2006) Endothelial dysfunction: a comprehensive appraisal. Cardiovasc Diabetol 5:4PubMedCrossRefGoogle Scholar
  27. 27.
    Richardson MR, Lai X, Witzmann FA, Yoder MC (2010) Venous and arterial endothelial proteomics: mining for markers and mechanisms of endothelial diversity. Expert Rev Proteomics 7(6):823–831. doi: 10.1586/epr.10.92 PubMedCrossRefGoogle Scholar
  28. 28.
    dela Paz NG, D’Amore PA (2009) Arterial versus venous endothelial cells. Cell Tissue Res 335(1):5–16. doi: 10.1007/s00441-008-0706-5 PubMedCrossRefGoogle Scholar
  29. 29.
    Peters K, Kamp G, Berz A, Unger RE, Barth S, Salamon A, Rychly J, Kirkpatrick CJ (2009) Changes in human endothelial cell energy metabolic capacities during in vitro cultivation. The role of “aerobic glycolysis” and proliferation. Cell Physiol Biochem 4(5):483–492CrossRefGoogle Scholar
  30. 30.
    Dobrina A, Rossi F (1983) Metabolic properties of freshly isolated bovine endothelial cells. Biochim Biophys Acta 762(2):295–301PubMedCrossRefGoogle Scholar
  31. 31.
    Quintero M, Colombo SL, Godfrey A, Moncada S (2006) Mitochondria as signaling organelles in the vascular endothelium. Proc Natl Acad Sci USA 103(14):5379–5384. pii:0601026103PubMedCrossRefGoogle Scholar
  32. 32.
    Krutzfeldt A, Spahr R, Mertens S, Siegmund B, Piper HM (1990) Metabolism of exogenous substrates by coronary endothelial cells in culture. J Mol Cell Cardiol 22(12):1393–1404. pii:0022-2828(90)90984-APubMedCrossRefGoogle Scholar
  33. 33.
    Nisoli E, Carruba MO (2006) Nitric oxide and mitochondrial biogenesis. J Cell Sci 119(Pt 14):2855–2862. pii: 119/14/2855PubMedCrossRefGoogle Scholar
  34. 34.
    Hagen T, Taylor CT, Lam F, Moncada S (2003) Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1alpha. Science 302(5652):1975–1978. doi: 10.1126/science.1088805302/5652/1975 PubMedCrossRefGoogle Scholar
  35. 35.
    Fraisl P, Mazzone M, Schmidt T, Carmeliet P (2009) Regulation of angiogenesis by oxygen and metabolism. Dev Cell 16(2):167–179. doi: 10.1016/S0965-1748(96)00031-8 PubMedCrossRefGoogle Scholar
  36. 36.
    Kulshreshtha R, Ferracin M, Wojcik SE, Garzon R, Alder H, Agosto-Perez FJ, Davuluri R, Liu CG, Croce CM, Negrini M, Calin GA, Ivan M (2007) A microRNA signature of hypoxia. Mol Cell Biol 27(5):1859–1867PubMedCrossRefGoogle Scholar
  37. 37.
    Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J (2009) MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab 10(4):273–284. pii:S1550-4131(09)00265-4PubMedCrossRefGoogle Scholar
  38. 38.
    Fasanaro P, D’Alessandra Y, Di Stefano V, Melchionna R, Romani S, Pompilio G, Capogrossi MC, Martelli F (2008) MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine-kinase ligand Ephrin-A3. J Biol Chem 283(23):15878–15883Google Scholar
  39. 39.
    Chen Z, Li Y, Zhang H, Huang P, Luthra R (2010) Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression. Oncogene 29(30):4362–4368. pii:onc2010193PubMedCrossRefGoogle Scholar
  40. 40.
    Chan YC, Khanna S, Roy S, Sen CK (2011) miR-200b targets Ets-1 and is down-regulated by hypoxia to induce angiogenic response of endothelial cells. J Biol Chem 286(3):2047–2056. doi: 10.1074/jbc.M110.158790 PubMedCrossRefGoogle Scholar
  41. 41.
    Zhang DX, Gutterman DD (2007) Mitochondrial reactive oxygen species-mediated signaling in endothelial cells. Am J Physiol Heart Circ Physiol 292(5):H2023–H2031. doi: 10.1152/ajpheart.01283.2006 PubMedCrossRefGoogle Scholar
  42. 42.
    Ding Y, Vaziri ND, Coulson R, Kamanna VS, Roh DD (2000) Effects of simulated hyperglycemia, insulin, and glucagon on endothelial nitric oxide synthase expression. Am J Physiol Endocrinol Metab 279(1):E11–E17PubMedGoogle Scholar
  43. 43.
    Du X, Edelstein D, Obici S, Higham N, Zou MH, Brownlee M (2006) Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J Clin Investig 116(4):1071–1080PubMedCrossRefGoogle Scholar
  44. 44.
    Kim JA, Montagnani M, Koh KK, Quon MJ (2006) Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 113(15):1888–1904PubMedCrossRefGoogle Scholar
  45. 45.
    Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54(6):1615–1625PubMedCrossRefGoogle Scholar
  46. 46.
    Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404(6779):787–790PubMedCrossRefGoogle Scholar
  47. 47.
    Quagliaro L, Piconi L, Assaloni R, Da Ros R, Szabo C, Ceriello A (2007) Primary role of superoxide anion generation in the cascade of events leading to endothelial dysfunction and damage in high glucose treated HUVEC. Nutr Metab Cardiovasc Dis 17(4):257–267PubMedCrossRefGoogle Scholar
  48. 48.
    Kamal K, Du W, Mills I, Sumpio BE (1998) Antiproliferative effect of elevated glucose in human microvascular endothelial cells. J Cell Biochem 71(4):491–501PubMedCrossRefGoogle Scholar
  49. 49.
    Varma S, Lal BK, Zheng R, Breslin JW, Saito S, Pappas PJ, Hobson RW 2nd, Duran WN (2005) Hyperglycemia alters PI3 k and Akt signaling and leads to endothelial cell proliferative dysfunction. Am J Physiol 289(4):H1744–H1751Google Scholar
  50. 50.
    Piconi L, Quagliaro L, Assaloni R, Da Ros R, Maier A, Zuodar G, Ceriello A (2006) Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction. Diabetes/Metab Res Rev 22(3):198–203CrossRefGoogle Scholar
  51. 51.
    Yu P, Yu DM, Qi JC, Wang J, Zhang QM, Zhang JY, Tang YZ, Xing QL, Li MZ (2006) High d-glucose alters PI3 K and Akt signaling and leads to endothelial cell migration, proliferation and angiogenesis dysfunction. Zhonghua yi xue za zhi 86(48):3425–3430PubMedGoogle Scholar
  52. 52.
    Hamuro M, Polan J, Natarajan M, Mohan S (2002) High glucose induced nuclear factor kappa B mediated inhibition of endothelial cell migration. Atherosclerosis 162(2):277–287PubMedCrossRefGoogle Scholar
  53. 53.
    Ho FM, Lin WW, Chen BC, Chao CM, Yang CR, Lin LY, Lai CC, Liu SH, Liau CS (2006) High glucose-induced apoptosis in human vascular endothelial cells is mediated through NF-kappaB and c-Jun NH2-terminal kinase pathway and prevented by PI3 K/Akt/eNOS pathway. Cell Signal 18(3):391–399PubMedCrossRefGoogle Scholar
  54. 54.
    Sheu ML, Ho FM, Yang RS, Chao KF, Lin WW, Lin-Shiau SY, Liu SH (2005) High glucose induces human endothelial cell apoptosis through a phosphoinositide 3-kinase-regulated cyclooxygenase-2 pathway. Arterioscler Thromb Vasc Biol 25(3):539–545PubMedCrossRefGoogle Scholar
  55. 55.
    Guo X, Chen LW, Liu WL, Guo ZG (2000) High glucose inhibits expression of inducible and constitutive nitric oxide synthase in bovine aortic endothelial cells. Acta Pharmacol Sin 21(4):325–328PubMedGoogle Scholar
  56. 56.
    Salt IP, Morrow VA, Brandie FM, Connell JM, Petrie JR (2003) High glucose inhibits insulin-stimulated nitric oxide production without reducing endothelial nitric-oxide synthase Ser1177 phosphorylation in human aortic endothelial cells. J Biol Chem 278(21):18791–18797PubMedCrossRefGoogle Scholar
  57. 57.
    Schnyder B, Pittet M, Durand J, Schnyder-Candrian S (2002) Rapid effects of glucose on the insulin signaling of endothelial NO generation and epithelial Na transport. Am J Physiol Endocrinol Metab 282(1):E87–E94PubMedGoogle Scholar
  58. 58.
    Srinivasan S, Hatley ME, Bolick DT, Palmer LA, Edelstein D, Brownlee M, Hedrick CC (2004) Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells. Diabetologia 47(10):1727–1734PubMedCrossRefGoogle Scholar
  59. 59.
    Altannavch TS, Roubalova K, Kucera P, Andel M (2004) Effect of high glucose concentrations on expression of ELAM-1, VCAM-1 and ICAM-1 in HUVEC with and without cytokine activation. Physiol Res 53(1):77–82PubMedGoogle Scholar
  60. 60.
    Haubner F, Lehle K, Munzel D, Schmid C, Birnbaum DE, Preuner JG (2007) Hyperglycemia increases the levels of vascular cellular adhesion molecule-1 and monocyte-chemoattractant-protein-1 in the diabetic endothelial cell. Biochem Biophys Res Commun 360(3):560–565PubMedCrossRefGoogle Scholar
  61. 61.
    Kado S, Wakatsuki T, Yamamoto M, Nagata N (2001) Expression of intercellular adhesion molecule-1 induced by high glucose concentrations in human aortic endothelial cells. Life Sci 68(7):727–737PubMedCrossRefGoogle Scholar
  62. 62.
    Quagliaro L, Piconi L, Assaloni R, Da Ros R, Maier A, Zuodar G, Ceriello A (2005) Intermittent high glucose enhances ICAM-1, VCAM-1 and E-selectin expression in human umbilical vein endothelial cells in culture: the distinct role of protein kinase C and mitochondrial superoxide production. Atherosclerosis 183(2):259–267PubMedCrossRefGoogle Scholar
  63. 63.
    Gosmanov AR, Stentz FB, Kitabchi AE (2006) De novo emergence of insulin-stimulated glucose uptake in human aortic endothelial cells incubated with high glucose. Am J Physiol Endocrinol Metab 290(3):E516–E522PubMedCrossRefGoogle Scholar
  64. 64.
    Mann GE, Yudilevich DL, Sobrevia L (2003) Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells. Physiol Rev 83(1):183–252. doi: 10.1152/physrev.00022.2002 PubMedGoogle Scholar
  65. 65.
    Wang XH, Qian RZ, Zhang W, Chen SF, Jin HM, Hu RM (2009) MicroRNA-320 expression in myocardial microvascular endothelial cells and its relationship with insulin-like growth factor-1 in type 2 diabetic rats. Clin Exp Pharmacol Physiol 36(2):181–188PubMedCrossRefGoogle Scholar
  66. 66.
    Schaar DG, Medina DJ, Moore DF, Strair RK, Ting Y (2009) miR-320 targets transferrin receptor 1 (CD71) and inhibits cell proliferation. Exp Hematol 37(2):245–255 doi: 10.1016/j.exphem.2008.10.002 PubMedCrossRefGoogle Scholar
  67. 67.
    Ling HY, Ou HS, Feng SD, Zhang XY, Tuo QH, Chen LX, Zhu BY, Gao ZP, Tang CK, Yin WD, Zhang L, Liao DF (2009) Changes in microRNA profile and effects of miR-320 in insulin-resistant 3T3-L1 adipocytes. Clin Exp Pharmacol Physiol 36(9):e32–e39Google Scholar
  68. 68.
    Ren XP, Wu J, Wang X, Sartor MA, Qian J, Jones K, Nicolaou P, Pritchard TJ, Fan GC (2009) MicroRNA-320 is involved in the regulation of cardiac ischemia/reperfusion injury by targeting heat-shock protein 20. Circulation 119(17):2357–2366PubMedCrossRefGoogle Scholar
  69. 69.
    Duan H, Jiang Y, Zhang H, Wu Y (2009) MiR-320 and miR-494 affect cell cycles of primary murine bronchial epithelial cells exposed to benzo[a]pyrene. Toxicol In Vitro 24(3):928–935Google Scholar
  70. 70.
    Chen L, Yan HX, Yang W, Hu L, Yu LX, Liu Q, Li L, Huang DD, Ding J, Shen F, Zhou WP, Wu MC, Wang HY (2009) The role of microRNA expression pattern in human intrahepatic cholangiocarcinoma. J Hepatol 50(2):358–369. doi: 10.1016/j.jhep.2008.09.015 PubMedCrossRefGoogle Scholar
  71. 71.
    Schepeler T, Reinert JT, Ostenfeld MS, Christensen LL, Silahtaroglu AN, Dyrskjot L, Wiuf C, Sorensen FJ, Kruhoffer M, Laurberg S, Kauppinen S, Orntoft TF, Andersen CL (2008) Diagnostic and prognostic microRNAs in stage II colon cancer. Cancer Res 68(15):6416–6424. doi: 10.1158/0008-5472 PubMedCrossRefGoogle Scholar
  72. 72.
    Yan LX, Huang XF, Shao Q, Huang MY, Deng L, Wu QL, Zeng YX, Shao JY (2008) MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA (New York NY) 14(11):2348–2360. doi: 10.1261/rna.1034808 CrossRefGoogle Scholar
  73. 73.
    Gao W, Shen H, Liu L, Xu J, Shu Y (2010) MiR-21 overexpression in human primary squamous cell lung carcinoma is associated with poor patient prognosis. J Cancer Res Clin Oncol. doi: 10.1007/s00432-010-0918-4
  74. 74.
    Lee KH, Lotterman C, Karikari C, Omura N, Feldmann G, Habbe N, Goggins MG, Mendell JT, Maitra A (2009) Epigenetic silencing of MicroRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer. Pancreatology 9(3):293–301. doi: 10.1159/000186051 PubMedCrossRefGoogle Scholar
  75. 75.
    Li Y, Song YH, Li F, Yang T, Lu YW, Geng YJ (2009) MicroRNA-221 regulates high glucose-induced endothelial dysfunction. Biochem Biophys Res Commun 381(1):81–83PubMedCrossRefGoogle Scholar
  76. 76.
    Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K, Mercatanti A, Hammond S, Rainaldi G (2006) MicroRNAs modulate the angiogenic properties of HUVECs. Blood 108(9):3068–3071PubMedCrossRefGoogle Scholar
  77. 77.
    Togliatto G, Trombetta A, Dentelli P, Rosso A, Brizzi MF (2011) MIR221/MIR222-driven post-transcriptional regulation of P27KIP1 and P57KIP2 is crucial for high-glucose- and AGE-mediated vascular cell damage. Diabetologia 54(7):1930–1940. doi: 10.1007/s00125-011-2125-5 PubMedCrossRefGoogle Scholar
  78. 78.
    Herrera BM, Lockstone HE, Taylor JM, Wills QF, Kaisaki PJ, Barrett A, Camps C, Fernandez C, Ragoussis J, Gauguier D, McCarthy MI, Lindgren CM (2009) MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of type 2 diabetes. BMC Med Genomics 2:54PubMedCrossRefGoogle Scholar
  79. 79.
    Caporali A, Meloni M, Vollenkle C, Bonci D, Sala-Newby GB, Addis R, Spinetti G, Losa S, Masson R, Baker AH, Agami R, le Sage C, Condorelli G, Madeddu P, Martelli F, Emanueli C (2011) Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia. Circulation. doi: 10.1161/CIRCULATIONAHA.110.952325
  80. 80.
    Jiang Q, Feng MG, Mo YY (2009) Systematic validation of predicted microRNAs for cyclin D1. BMC Cancer 9:194. doi: 10.1186/1471-2407-9-194 PubMedCrossRefGoogle Scholar
  81. 81.
    Sarkar S, Dey BK, Dutta A (2010) MiR-322/424 and -503 are induced during muscle differentiation and promote cell cycle quiescence and differentiation by down-regulation of Cdc25A. Mol Biol Cell 21(13):2138–2149. doi: 10.1158/0008-5472 PubMedCrossRefGoogle Scholar
  82. 82.
    Vogel RA, Corretti MC, Gellman J (1998) Cholesterol, cholesterol lowering, and endothelial function. Prog Cardiovasc Dis 41(2):117–136. doi: 10.1016/S0033-0620(98)80008-X PubMedCrossRefGoogle Scholar
  83. 83.
    Hennig B, Toborek M, McClain CJ (2001) High-energy diets, fatty acids and endothelial cell function: implications for atherosclerosis. J Am Coll Nutr 20(2 Suppl):97–105PubMedGoogle Scholar
  84. 84.
    Zilversmit DB (1995) Atherogenic nature of triglycerides, post-prandial lipidemia, and triglyceride-rich remnant lipoproteins. Clin Chem 41(1):153–158PubMedGoogle Scholar
  85. 85.
    Wang L, Gill R, Pedersen TL, Higgins LJ, Newman JW, Rutledge JC (2009) Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation. J Lipid Res 50(2):204–213. doi: 10.1194/jlr.M700505-JLR200 PubMedCrossRefGoogle Scholar
  86. 86.
    Kalinowski L, Malinski T (2004) Endothelial NADH/NADPH-dependent enzymatic sources of superoxide production: relationship to endothelial dysfunction. Acta Biochim Pol 51(2):459–469. pii:035001459PubMedGoogle Scholar
  87. 87.
    Kawashima S, Yokoyama M (2004) Dysfunction of endothelial nitric oxide synthase and atherosclerosis. Arterioscler Thromb Vasc Biol 24(6):998–1005. doi: 10.1161/01.ATV.0000125114.88079.96 PubMedCrossRefGoogle Scholar
  88. 88.
    Witztum JL (1991) The role of oxidized LDL in atherosclerosis. Adv Exp Med Biol 285:353–365PubMedGoogle Scholar
  89. 89.
    Liao JK, Shin WS, Lee WY, Clark SL (1995) Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem 270(1):319–324PubMedCrossRefGoogle Scholar
  90. 90.
    Seibold S, Schurle D, Heinloth A, Wolf G, Wagner M, Galle J (2004) Oxidized LDL induces proliferation and hypertrophy in human umbilical vein endothelial cells via regulation of p27Kip1 expression: role of RhoA. J Am Soc Nephrol 15(12):3026–3034PubMedCrossRefGoogle Scholar
  91. 91.
    Rayner KJ, Suarez Y, Davalos A, Parathath S, Fitzgerald ML, Tamehiro N, Fisher EA, Moore KJ, Fernandez-Hernando C (2010) MiR-33 contributes to the regulation of cholesterol homeostasis. Science (New York, NY) 328(5985):1570–1573. doi: 10.1126/science.1189862 CrossRefGoogle Scholar
  92. 92.
    Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Cohen DE, Gerszten RE, Naar AM (2010) MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science (New York NY) 328(5985):1566–1569. doi: 10.1126/science.1189123 CrossRefGoogle Scholar
  93. 93.
    Zeng L, Liao H, Liu Y, Lee TS, Zhu M, Wang X, Stemerman MB, Zhu Y, Shyy JY (2004) Sterol-responsive element-binding protein (SREBP) 2 down-regulates ATP-binding cassette transporter A1 in vascular endothelial cells: a novel role of SREBP in regulating cholesterol metabolism. J Biol Chem 279(47):48801–48807. doi: 10.1074/jbc.M407817200M407817200 PubMedCrossRefGoogle Scholar
  94. 94.
    Horie T, Ono K, Horiguchi M, Nishi H, Nakamura T, Nagao K, Kinoshita M, Kuwabara Y, Marusawa H, Iwanaga Y, Hasegawa K, Yokode M, Kimura T, Kita T (2010) MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo. Proc Natl Acad Sci USA 107(40):17321–17326. doi: 10.1073/pnas.1008499107 PubMedCrossRefGoogle Scholar
  95. 95.
    Li D, Yang P, Xiong Q, Song X, Yang X, Liu L, Yuan W, Rui YC (2010) MicroRNA-125a/b-5p inhibits endothelin-1 expression in vascular endothelial cells. J Hypertens. doi: 10.1097/HJH.0b013e32833a4922
  96. 96.
    Chen T, Huang Z, Wang L, Wang Y, Wu F, Meng S, Wang C (2009) MicroRNA-125a–5p partly regulates the inflammatory response, lipid uptake, and ORP9 expression in oxLDL-stimulated monocyte/macrophages. Cardiovasc Res 83(1):131–139. doi: 10.1093/cvr/cvp121 PubMedCrossRefGoogle Scholar
  97. 97.
    Smith DL Jr, Nagy TR, Allison DB (2010) Calorie restriction: what recent results suggest for the future of ageing research. Eur J Clin Invest 40(5):440–450. pii:ECI2276PubMedCrossRefGoogle Scholar
  98. 98.
    Blagosklonny MV (2010) Calorie restriction: decelerating mTOR-driven aging from cells to organisms (including humans). Cell Cycle 9(4):683–688. doi: 10.4161/cc.9.4.10766 PubMedCrossRefGoogle Scholar
  99. 99.
    Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi E, Moncada S, Carruba MO (2005) Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310(5746):314–317. doi: 10.1126/science.1117728 PubMedCrossRefGoogle Scholar
  100. 100.
    Ghosh S, George S, Roy U, Ramachandran D, Kolthur-Seetharam U (2010) NAD: a master regulator of transcription. Biochim Biophys Acta 1799(10–12):681–693. doi: 10.1016/j.bbagrm.2010.08.002 PubMedGoogle Scholar
  101. 101.
    Ota H, Akishita M, Eto M, Iijima K, Kaneki M, Ouchi Y (2007) Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J Mol Cell Cardiol 43(5):571–579. doi: 10.1016/S0022-2828(03)00120-2 PubMedCrossRefGoogle Scholar
  102. 102.
    Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F, Haendeler J, Mione M, Dejana E, Alt FW, Zeiher AM, Dimmeler S (2007) SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev 21(20):2644–2658. doi: 10.1101/gad.435107 PubMedCrossRefGoogle Scholar
  103. 103.
    Menghini R, Casagrande V, Cardellini M, Martelli E, Terrinoni A, Amati F, Vasa-Nicotera M, Ippoliti A, Novelli G, Melino G, Lauro R, Federici M (2009) MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation 120(15):1524–1532. doi: 10.1161/CIRCULATIONAHA.109.864629 PubMedCrossRefGoogle Scholar
  104. 104.
    Hermeking H (2010) The miR-34 family in cancer and apoptosis. Cell Death Differ 17(2):193–199 10.1234/12345678PubMedCrossRefGoogle Scholar
  105. 105.
    Ito T, Yagi S, Yamakuchi M (2010) MicroRNA-34a regulation of endothelial senescence. Biochem Biophys Res Commun 398(4):735–740. pii:S0006-291X(10)01314-8PubMedCrossRefGoogle Scholar
  106. 106.
    Ferrara N, Chen H, Davis-Smyth T, Gerber HP, Nguyen TN, Peers D, Chisholm V, Hillan KJ, Schwall RH (1998) Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med 4(3):336–340PubMedCrossRefGoogle Scholar
  107. 107.
    Risau W (1997) Mechanisms of angiogenesis. Nature 386(6626):671–674PubMedCrossRefGoogle Scholar
  108. 108.
    Ribatti D, Nico B, Crivellato E, Roccaro AM, Vacca A (2007) The history of the angiogenic switch concept. Leukemia 21(1):44–52PubMedCrossRefGoogle Scholar
  109. 109.
    Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2(10):737–744PubMedCrossRefGoogle Scholar
  110. 110.
    Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364PubMedCrossRefGoogle Scholar
  111. 111.
    Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161(6):1163–1177. doi: 10.1083/jcb.200302047 PubMedCrossRefGoogle Scholar
  112. 112.
    Bussolino F, Mantovani A, Persico G (1997) Molecular mechanisms of blood vessel formation. Trends Biochem Sci 22(7):251–256PubMedCrossRefGoogle Scholar
  113. 113.
    Whitelock JM, Murdoch AD, Iozzo RV, Underwood PA (1996) The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases. J Biol Chem 271(17):10079–10086PubMedCrossRefGoogle Scholar
  114. 114.
    Gately S, Twardowski P, Stack MS, Cundiff DL, Grella D, Castellino FJ, Enghild J, Kwaan HC, Lee F, Kramer RA, Volpert O, Bouck N, Soff GA (1997) The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc Natl Acad Sci USA 94(20):10868–10872PubMedCrossRefGoogle Scholar
  115. 115.
    Ruegg C, Alghisi GC (2010) Vascular integrins: therapeutic and imaging targets of tumor angiogenesis. Recent Results Cancer Res 180:83–101. doi: 10.1007/978-3-540-78281-0_6 PubMedCrossRefGoogle Scholar
  116. 116.
    Pries AR, Hopfner M, le Noble F, Dewhirst MW, Secomb TW (2010) The shunt problem: control of functional shunting in normal and tumour vasculature. Nat Rev 10(8):587–593. doi: 10.1038/nrc2895 CrossRefGoogle Scholar
  117. 117.
    Abdollahi A, Schwager C, Kleeff J, Esposito I, Domhan S, Peschke P, Hauser K, Hahnfeldt P, Hlatky L, Debus J, Peters JM, Friess H, Folkman J, Huber PE (2007) Transcriptional network governing the angiogenic switch in human pancreatic cancer. Proc Natl Acad Sci USA 104(31):12890–12895PubMedCrossRefGoogle Scholar
  118. 118.
    Almog N, Ma L, Raychowdhury R, Schwager C, Erber R, Short S, Hlatky L, Vajkoczy P, Huber PE, Folkman J, Abdollahi A (2009) Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype. Cancer Res 69(3):836–844. doi: 10.1158/0008-5472.CAN-08-2590 PubMedCrossRefGoogle Scholar
  119. 119.
    Yang WJ, Yang DD, Na S, Sandusky GE, Zhang Q, Zhao G (2005) Dicer is required for embryonic angiogenesis during mouse development. J Biol Chem 280(10):9330–9335PubMedCrossRefGoogle Scholar
  120. 120.
    Otsuka M, Zheng M, Hayashi M, Lee JD, Yoshino O, Lin S, Han J (2008) Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice. J Clin Investig 118(5):1944–1954PubMedCrossRefGoogle Scholar
  121. 121.
    Suarez Y, Fernandez-Hernando C, Pober JS, Sessa WC (2007) Dicer-dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res 100(8):1164–1173PubMedCrossRefGoogle Scholar
  122. 122.
    Kuehbacher A, Urbich C, Zeiher AM, Dimmeler S (2007) Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ Res 101(1):59–68PubMedCrossRefGoogle Scholar
  123. 123.
    Shilo S, Roy S, Khanna S, Sen CK (2008) Evidence for the involvement of miRNA in redox regulated angiogenic response of human microvascular endothelial cells. Arterioscler Thromb Vasc Biol 28(3):471–477PubMedCrossRefGoogle Scholar
  124. 124.
    Chen Y, Banda M, Speyer CL, Smith JS, Rabson AB, Gorski DH (2010) Regulation of the expression and activity of the anti-angiogenic homeobox gene GAX/MEOX2 by ZEB2 and microRNA-221. Mol Cell Biol 30(15):3902–3913. doi: 10.1128/MCB.01237-09 PubMedCrossRefGoogle Scholar
  125. 125.
    Gorski DH, Leal AJ (2003) Inhibition of endothelial cell activation by the homeobox gene Gax. J Surg Res 111(1):91–99PubMedCrossRefGoogle Scholar
  126. 126.
    Patel S, Leal AD, Gorski DH (2005) The homeobox gene Gax inhibits angiogenesis through inhibition of nuclear factor-kappaB-dependent endothelial cell gene expression. Cancer Res 65(4):1414–1424PubMedCrossRefGoogle Scholar
  127. 127.
    Chen Y, Gorski DH (2008) Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates anti-angiogenic homeobox genes GAX and HOXA5. Blood 111(3):1217–1226PubMedCrossRefGoogle Scholar
  128. 128.
    Dentelli P, Rosso A, Orso F, Olgasi C, Taverna D, Brizzi MF (2010) microRNA-222 controls neovascularization by regulating signal transducer and activator of transcription 5A expression. Arterioscler Thromb Vasc Biol 30(8):1562–1568. doi: 10.1161/ATVBAHA.110.206201 PubMedCrossRefGoogle Scholar
  129. 129.
    Gatt ME, Zhao JJ, Ebert MS, Zhang Y, Chu Z, Mani M, Gazit R, Carrasco DE, Dutta-Simmons J, Adamia S, Minvielle S, Tai YT, Munshi NC, Avet-Loiseau H, Anderson KC, Carrasco DR (2010) MicroRNAs 15a/16-1 function as tumor suppressor genes in multiple myeloma. Blood. doi: 10.1182/blood-2009-11-253294
  130. 130.
    Karaa ZS, Iacovoni JS, Bastide A, Lacazette E, Touriol C, Prats H (2009) The VEGF IRESes are differentially susceptible to translation inhibition by miR-16. RNA 15(2):249–254. doi: 10.1210/me.15.12.2197 PubMedCrossRefGoogle Scholar
  131. 131.
    Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, Burchfield J, Fox H, Doebele C, Ohtani K, Chavakis E, Potente M, Tjwa M, Urbich C, Zeiher AM, Dimmeler S (2009) MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science (New York, NY) 324(5935):1710–1713CrossRefGoogle Scholar
  132. 132.
    Anand S, Majeti BK, Acevedo LM, Murphy EA, Mukthavaram R, Scheppke L, Huang M, Shields DJ, Lindquist JN, Lapinski PE, King PD, Weis SM, Cheresh DA (2010) MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis. Nat Med 16(8):909–914. doi: 10.1038/nm.2186 PubMedCrossRefGoogle Scholar
  133. 133.
    Wurdinger T, Tannous BA, Saydam O, Skog J, Grau S, Soutschek J, Weissleder R, Breakefield XO, Krichevsky AM (2008) miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells. Cancer Cell 14(5):382–393PubMedCrossRefGoogle Scholar
  134. 134.
    Fang L, Deng Z, Shatseva T, Yang J, Peng C, Du WW, Yee AJ, Ang LC, He C, Shan SW, Yang BB (2010) MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-beta8. Oncogene. doi: 10.1038/onc.2010.465
  135. 135.
    Lee DY, Deng Z, Wang CH, Yang BB (2007) MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression. Proc Natl Acad Sci USA 104(51):20350–20355PubMedCrossRefGoogle Scholar
  136. 136.
    Mendell JT (2008) miRiad roles for the miR-17–92 cluster in development and disease. Cell 133(2):217–222PubMedCrossRefGoogle Scholar
  137. 137.
    Suarez Y, Fernandez-Hernando C, Yu J, Gerber SA, Harrison KD, Pober JS, Iruela-Arispe ML, Merkenschlager M, Sessa WC (2008) Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis. Proc Natl Acad Sci USA 105(37):14082–14087PubMedCrossRefGoogle Scholar
  138. 138.
    Dews M, Homayouni A, Yu D, Murphy D, Sevignani C, Wentzel E, Furth EE, Lee WM, Enders GH, Mendell JT, Thomas-Tikhonenko A (2006) Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet 38(9):1060–1065PubMedCrossRefGoogle Scholar
  139. 139.
    Dews M, Fox JL, Hultine S, Sundaram P, Wang W, Liu YY, Furth E, Enders GH, El-Deiry W, Schelter JM, Cleary MA, Thomas-Tikhonenko A (2010) The Myc-miR-17 92 axis blunts TGFβ signaling and production of multiple TGFβ-dependent anti-angiogenic factors. Cancer Res 70(20):8233–8246. doi: 10.1158/0008-5472.CAN-10-2412 PubMedCrossRefGoogle Scholar
  140. 140.
    Saito Y, Friedman JM, Chihara Y, Egger G, Chuang JC, Liang G (2009) Epigenetic therapy upregulates the tumor suppressor microRNA-126 and its host gene EGFL7 in human cancer cells. Biochem Biophys Res Commun 379(3):726–731. doi: 10.1016/j.bbrc.2008.12.098 PubMedCrossRefGoogle Scholar
  141. 141.
    Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ (2008) MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci USA 105(5):1516–1521PubMedCrossRefGoogle Scholar
  142. 142.
    Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DY, Srivastava D (2008) miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 15(2):272–284PubMedCrossRefGoogle Scholar
  143. 143.
    Kuhnert F, Mancuso MR, Hampton J, Stankunas K, Asano T, Chen CZ, Kuo CJ (2008) Attribution of vascular phenotypes of the murine Egfl7 locus to the microRNA miR-126. Development 135(24):3989–3993. doi: 10.1242/dev.029736 PubMedCrossRefGoogle Scholar
  144. 144.
    Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, Richardson JA, Bassel-Duby R, Olson EN (2008) The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell 15(2):261–271PubMedCrossRefGoogle Scholar
  145. 145.
    Zou J, Li WQ, Li Q, Li XQ, Zhang JT, Liu GQ, Chen J, Qiu XX, Tian FJ, Wang ZZ, Zhu N, Qin YW, Shen B, Liu TX, Jing Q (2011) Two functional microRNA-126 s repress a novel target gene p21-activated kinase 1 to regulate vascular integrity in zebrafish. Circ Res 108(2):201–209. doi: 10.1161/CIRCRESAHA.110.225045 PubMedCrossRefGoogle Scholar
  146. 146.
    Schmidt M, Paes K, De Maziere A, Smyczek T, Yang S, Gray A, French D, Kasman I, Klumperman J, Rice DS, Ye W (2007) EGFL7 regulates the collective migration of endothelial cells by restricting their spatial distribution. Development 134(16):2913–2923. doi: 10.1242/dev.002576 PubMedCrossRefGoogle Scholar
  147. 147.
    Nicoli S, Standley C, Walker P, Hurlstone A, Fogarty KE, Lawson ND (2010) MicroRNA-mediated integration of haemodynamics and VEGF signalling during angiogenesis. Nature 464(7292):1196–1200. doi: 10.1038/nature08889 PubMedCrossRefGoogle Scholar
  148. 148.
    Meister J, Schmidt MH (2010) miR-126 and miR-126*: new players in cancer. ScientificWorld Journal 10:2090–2100. doi: 10.1100/tsw.2010.198 PubMedCrossRefGoogle Scholar
  149. 149.
    Zhang J, Du YY, Lin YF, Chen YT, Yang L, Wang HJ, Ma D (2008) The cell growth suppressor, mir-126, targets IRS-1. Biochem Biophys Res Commun 377(1):136–140PubMedCrossRefGoogle Scholar
  150. 150.
    Liu B, Peng XC, Zheng XL, Wang J, Qin YW (2009) MiR-126 restoration down-regulate VEGF and inhibit the growth of lung cancer cell lines in vitro and in vivo. Lung Cancer 66(2):169–175. doi: 10.1016/j.lungcan.2009.01.010 PubMedCrossRefGoogle Scholar
  151. 151.
    Zhu N, Zhang D, Xie H, Zhou Z, Chen H, Hu T, Bai Y, Shen Y, Yuan W, Jing Q, Qin Y (2011) Endothelial-specific intron-derived miR-126 is down-regulated in human breast cancer and targets both VEGFA and PIK3R2. Mol Cell Biochem 351(1–2):157–164. doi: 10.1007/s11010-011-0723-7 PubMedCrossRefGoogle Scholar
  152. 152.
    Crawford M, Brawner E, Batte K, Yu L, Hunter MG, Otterson GA, Nuovo G, Marsh CB, Nana-Sinkam SP (2008) MicroRNA-126 inhibits invasion in non-small cell lung carcinoma cell lines. Biochem Biophys Res Commun 373(4):607–612. doi: 10.1016/j.bbrc.2008.06.090 PubMedCrossRefGoogle Scholar
  153. 153.
    Feng R, Chen X, Yu Y, Su L, Yu B, Li J, Cai Q, Yan M, Liu B, Zhu Z (2010) miR-126 functions as a tumour suppressor in human gastric cancer. Cancer Lett 298(1):50–63. doi: 10.1016/j.canlet.2010.06.004 PubMedCrossRefGoogle Scholar
  154. 154.
    Sun Y, Bai Y, Zhang F, Wang Y, Guo Y, Guo L (2010) miR-126 inhibits non-small cell lung cancer cells proliferation by targeting EGFL7. Biochem Biophys Res Commun 391(3):1483–1489. doi: 10.1016/j.bbrc.2009 PubMedCrossRefGoogle Scholar
  155. 155.
    Donnem T, Lonvik K, Eklo K, Berg T, Sorbye SW, Al-Shibli K, Al-Saad S, Andersen S, Stenvold H, Bremnes RM, Busund LT (2011) Independent and tissue-specific prognostic impact of miR-126 in nonsmall cell lung cancer: coexpression with vascular endothelial growth factor-A predicts poor survival. Cancer. doi: 10.1002/cncr.25907
  156. 156.
    Barshack I, Lithwick-Yanai G, Afek A, Rosenblatt K, Tabibian-Keissar H, Zepeniuk M, Cohen L, Dan H, Zion O, Strenov Y, Polak-Charcon S, Perelman M (2010) MicroRNA expression differentiates between primary lung tumors and metastases to the lung. Pathol Res Pract. pii:S0344-0338(10)00087-7Google Scholar
  157. 157.
    Gilad S, Meiri E, Yogev Y, Benjamin S, Lebanony D, Yerushalmi N, Benjamin H, Kushnir M, Cholakh H, Melamed N, Bentwich Z, Hod M, Goren Y, Chajut A (2008) Serum microRNAs are promising novel biomarkers. PLoS ONE 3(9):e3148. doi: 10.1371/journal.pone.0003148 PubMedCrossRefGoogle Scholar
  158. 158.
    Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, Mayr A, Weger S, Oberhollenzer F, Bonora E, Shah A, Willeit J, Mayr M (2010) Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res 107(6):810–817. doi: 10.1161/CIRCRESAHA.110.226357 PubMedCrossRefGoogle Scholar
  159. 159.
    Zhang Y, Liu D, Chen X, Li J, Li L, Bian Z, Sun F, Lu J, Yin Y, Cai X, Sun Q, Wang K, Ba Y, Wang Q, Wang D, Yang J, Liu P, Xu T, Yan Q, Zhang J, Zen K, Zhang CY (2010) Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell 39(1):133–144. doi: 10.1016/S1097-2765(03)00100-X PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  1. 1.Scuola Superiore Sant’AnnaPisaItaly
  2. 2.Istituto di Fisiologia Clinica, CNRPisaItaly
  3. 3.Istituto Toscano TumoriFlorenceItaly

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