Advertisement

Metabolism of Methylarginines and Angiogenesis

  • Hilda Tsang
  • Lucio Iannone
  • Beata Wojciak-StothardEmail author
Chapter

Abstract

Endogenously produced analogues of the amino acid arginine, monomethylarginine (l-NMMA), asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) play an important regulatory role in angiogenesis. This chapter provides an overview of the role of methylarginines and the methylarginine metabolising enzymes dimethylaminohydrolases (DDAH) on endothelial angiogenic responses in vitro and in vivo, in animal models, and in human disease. We also discuss molecular and cellular mechanisms involved, including nitric oxide (NO) pathway, transforming growth factor β (TGF-β) and Ras and Rho protein signalling.

Keywords

Angiogenesis Nitric oxide Methylarginines DDAH Endothelial 

Notes

Acknowledgements

The authors wish to thank Lisa Storck for her kind help in preparation of this chapter.

References

  1. 1.
    Dimmeler S, Hermann C, Galle J, Zeiher AM (1999) Upregulation of superoxide dismutase and nitric oxide synthase mediates the apoptosis-suppressive effects of shear stress on endothelial cells. Arterioscler Thromb Vasc Biol 19(3):656–664PubMedGoogle Scholar
  2. 2.
    Morbidelli L, Chang CH, Douglas JG, Granger HJ, Ledda F, Ziche M (1996) Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium. Am J Physiol 270(1 Pt 2):H411–H415PubMedGoogle Scholar
  3. 3.
    Murohara T, Witzenbichler B, Spyridopoulos I, Asahara T, Ding B, Sullivan A et al (1999) Role of endothelial nitric oxide synthase in endothelial cell migration. Arterioscler Thromb Vasc Biol 19(5):1156–1161PubMedGoogle Scholar
  4. 4.
    Ziche M, Parenti A, Ledda F, Dell’Era P, Granger HJ, Maggi CA et al (1997) Nitric oxide promotes proliferation and plasminogen activator production by coronary venular endothelium through endogenous bFGF. Circ Res 80(6):845–852PubMedGoogle Scholar
  5. 5.
    Babaei S, Teichert-Kuliszewska K, Monge JC, Mohamed F, Bendeck MP, Stewart DJ (1998) Role of nitric oxide in the angiogenic response in vitro to basic fibroblast growth factor. Circ Res 82(9):1007–1015PubMedGoogle Scholar
  6. 6.
    Papapetropoulos A, Garcia-Cardena G, Madri JA, Sessa WC (1997) Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Invest 100(12):3131–3139PubMedCentralPubMedGoogle Scholar
  7. 7.
    Dulak J, Jozkowicz A, Dembinska-Kiec A, Guevara I, Zdzienicka A, Zmudzinska-Grochot D et al (2000) Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 20(3):659–666PubMedGoogle Scholar
  8. 8.
    Amano K, Matsubara H, Iba O, Okigaki M, Fujiyama S, Imada T et al (2003) Enhancement of ischemia-induced angiogenesis by eNOS overexpression. Hypertension 41(1):156–162PubMedGoogle Scholar
  9. 9.
    Smith RS Jr, Lin KF, Agata J, Chao L, Chao J (2002) Human endothelial nitric oxide synthase gene delivery promotes angiogenesis in a rat model of hindlimb ischemia. Arterioscler Thromb Vasc Biol 22(8):1279–1285PubMedGoogle Scholar
  10. 10.
    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
  11. 11.
    Najbauer J, Johnson BA, Young AL, Aswad DW (1993) Peptides with sequences similar to glycine, arginine-rich motifs in proteins interacting with RNA are efficiently recognized by methyltransferase(s) modifying arginine in numerous proteins. J Biol Chem 268(14):10501–10509PubMedGoogle Scholar
  12. 12.
    Cheng D, Yadav N, King RW, Swanson MS, Weinstein EJ, Bedford MT (2004) Small molecule regulators of protein arginine methyltransferases. J Biol Chem 279(23):23892–23899PubMedGoogle Scholar
  13. 13.
    Bedford MT, Richard S (2005) Arginine methylation an emerging regulator of protein function. Mol Cell 18(3):263–272PubMedGoogle Scholar
  14. 14.
    Boisvert FM, Cote J, Boulanger MC, Cleroux P, Bachand F, Autexier C et al (2002) Symmetrical dimethylarginine methylation is required for the localization of SMN in Cajal bodies and pre-mRNA splicing. J Cell Biol 159(6):957–969PubMedGoogle Scholar
  15. 15.
    El-Andaloussi N, Valovka T, Toueille M, Hassa PO, Gehrig P, Covic M et al (2007) Methylation of DNA polymerase beta by protein arginine methyltransferase 1 regulates its binding to proliferating cell nuclear antigen. FASEB J 21(1):26–34PubMedGoogle Scholar
  16. 16.
    Pope AJ, Karuppiah K, Cardounel AJ (2009) Role of the PRMT-DDAH-ADMA axis in the regulation of endothelial nitric oxide production. Pharmacol Res 60(6):461–465PubMedCentralPubMedGoogle Scholar
  17. 17.
    Closs EI, Simon A, Vekony N, Rotmann A (2004) Plasma membrane transporters for arginine. J Nutr 134(10 Suppl):2752S–2759S, discussion 65S–67SPubMedGoogle Scholar
  18. 18.
    Vallance P, Leone A, Calver A, Collier J, Moncada S (1992) Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis. J Cardiovasc Pharmacol 20(Suppl 12):S60–S62PubMedGoogle Scholar
  19. 19.
    Cooke JP (2004) Asymmetrical dimethylarginine: the Uber marker? Circulation 109(15):1813–1818PubMedGoogle Scholar
  20. 20.
    Cardounel AJ, Cui H, Samouilov A, Johnson W, Kearns P, Tsai AL et al (2007) Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function. J Biol Chem 282(2):879–887PubMedGoogle Scholar
  21. 21.
    Achan V, Broadhead M, Malaki M, Whitley G, Leiper J, MacAllister R et al (2003) Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol 23(8):1455–1459PubMedGoogle Scholar
  22. 22.
    Nijveldt RJ, Teerlink T, Siroen MP, van Lambalgen AA, Rauwerda JA, van Leeuwen PA (2003) The liver is an important organ in the metabolism of asymmetrical dimethylarginine (ADMA). Clin Nutr 22(1):17–22PubMedGoogle Scholar
  23. 23.
    Wojciak-Stothard B, Torondel B, Zhao L, Renné T, Leiper JM (2009) Modulation of Rac1 activity by ADMA/DDAH regulates pulmonary endothelial barrier function. Mol Biol Cell 20(1):33–42. doi: 10.1091/mbc.E08-04-0395 PubMedCentralPubMedGoogle Scholar
  24. 24.
    Hu X, Xu X, Zhu G, Atzler D, Kimoto M, Chen J, Schwedhelm E, Lüneburg N, Böger RH, Zhang P, Chen Y (2009) Vascular endothelial-specific dimethylarginine dimethylaminohydrolase-1-deficient mice reveal that vascular endothelium plays an important role in removing asymmetric dimethylarginine. Circulation 120(22):2222–2229. doi: 10.1161/CIRCULATIONAHA.108.819912 PubMedCentralPubMedGoogle Scholar
  25. 25.
    Palm F, Onozato ML, Luo Z, Wilcox CS (2007) Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol 293(6):H3227–H3245PubMedGoogle Scholar
  26. 26.
    Fiedler LR, Bachetti T, Leiper J, Zachary I, Chen L, Renne T et al (2009) The ADMA/DDAH pathway regulates VEGF-mediated angiogenesis. Arterioscler Thromb Vasc Biol 29(12):2117–2124PubMedGoogle Scholar
  27. 27.
    Wojciak-Stothard B, Torondel B, Tsang LY, Fleming I, Fisslthaler B, Leiper JM et al (2007) The ADMA/DDAH pathway is a critical regulator of endothelial cell motility. J Cell Sci 120(Pt 6):929–942PubMedGoogle Scholar
  28. 28.
    Zhang P, Hu X, Xu X, Chen Y, Bache RJ (2011) Dimethylarginine dimethylaminohydrolase 1 modulates endothelial cell growth through nitric oxide and Akt. Arterioscler Thromb Vasc Biol 31(4):890–897PubMedCentralPubMedGoogle Scholar
  29. 29.
    Hu X, Atzler D, Xu X, Zhang P, Guo H, Lu Z et al (2011) Dimethylarginine dimethylaminohydrolase-1 is the critical enzyme for degrading the cardiovascular risk factor asymmetrical dimethylarginine. Arterioscler Thromb Vasc Biol 31(7):1540–1546PubMedCentralPubMedGoogle Scholar
  30. 30.
    Cooke JP (2003) NO and angiogenesis. Atheroscler Suppl 4(4):53–60PubMedGoogle Scholar
  31. 31.
    Jacobi J, Sydow K, von Degenfeld G, Zhang Y, Dayoub H, Wang B et al (2005) Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis. Circulation 111(11):1431–1438PubMedGoogle Scholar
  32. 32.
    Hasegawa K, Wakino S, Tatematsu S, Yoshioka K, Homma K, Sugano N et al (2007) Role of asymmetric dimethylarginine in vascular injury in transgenic mice overexpressing dimethylarginie dimethylaminohydrolase 2. Circ Res 101(2):e2–e10PubMedGoogle Scholar
  33. 33.
    Kostourou V, Robinson SP, Cartwright JE, Whitley GS (2002) Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis. Br J Cancer 87(6):673–680PubMedCentralPubMedGoogle Scholar
  34. 34.
    Matsumoto Y, Ueda S, Yamagishi S, Matsuguma K, Shibata R, Fukami K et al (2007) Dimethylarginine dimethylaminohydrolase prevents progression of renal dysfunction by inhibiting loss of peritubular capillaries and tubulointerstitial fibrosis in a rat model of chronic kidney disease. J Am Soc Nephrol 18(5):1525–1533PubMedGoogle Scholar
  35. 35.
    Shibata R, Ueda S, Yamagishi S, Kaida Y, Matsumoto Y, Fukami K et al (2009) Involvement of asymmetric dimethylarginine (ADMA) in tubulointerstitial ischemia in the early phase of diabetic nephropathy. Nephrol Dial Transplant 24(4):1162–1169PubMedGoogle Scholar
  36. 36.
    Smith CL, Birdsey GM, Anthony S, Arrigoni FI, Leiper JM, Vallance P (2003) Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype. Biochem Biophys Res Commun 308(4):984–989PubMedGoogle Scholar
  37. 37.
    Hasegawa K, Wakino S, Tanaka T, Kimoto M, Tatematsu S, Kanda T et al (2006) Dimethylarginine dimethylaminohydrolase 2 increases vascular endothelial growth factor expression through Sp1 transcription factor in endothelial cells. Arterioscler Thromb Vasc Biol 26(7):1488–1494PubMedGoogle Scholar
  38. 38.
    Thum T, Tsikas D, Stein S, Schultheiss M, Eigenthaler M, Anker SD et al (2005) Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. J Am Coll Cardiol 46(9):1693–1701PubMedGoogle Scholar
  39. 39.
    Achan V, Ho HK, Heeschen C, Stuehlinger M, Jang JJ, Kimoto M et al (2005) ADMA regulates angiogenesis: genetic and metabolic evidence. Vasc Med 10(1):7–14PubMedGoogle Scholar
  40. 40.
    Jang JJ, Ho HK, Kwan HH, Fajardo LF, Cooke JP (2000) Angiogenesis is impaired by hypercholesterolemia: role of asymmetric dimethylarginine. Circulation 102(12):1414–1419PubMedGoogle Scholar
  41. 41.
    Böger RH, Bode-Boger SM, Szuba A, Tsao PS, Chan JR, Tangphao O et al (1998) Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 98(18):1842–1847PubMedGoogle Scholar
  42. 42.
    Chobanyan-Jürgens K, Fuchs AJ, Tsikas D, Kanzelmeyer N, Das AM, Illsinger S et al (2012) Increased asymmetric dimethylarginine (ADMA) dimethylaminohydrolase (DDAH) activity in childhood hypercholesterolemia type II. Amino Acids 43(2):805–811PubMedGoogle Scholar
  43. 43.
    Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R (1994) ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb 14(1):133–140PubMedGoogle Scholar
  44. 44.
    Gallo O, Masini E, Morbidelli L, Franchi A, Fini-Storchi I, Vergari WA et al (1998) Role of nitric oxide in angiogenesis and tumor progression in head and neck cancer. J Natl Cancer Inst 90(8):587–596PubMedGoogle Scholar
  45. 45.
    Ronquist KG, Ronquist G, Larsson A, Carlsson L (2010) Proteomic analysis of prostate cancer metastasis-derived prostasomes. Anticancer Res 30(2):285–290PubMedGoogle Scholar
  46. 46.
    Kostourou V, Robinson SP, Whitley GS, Griffiths JR (2003) Effects of overexpression of dimethylarginine dimethylaminohydrolase on tumor angiogenesis assessed by susceptibility magnetic resonance imaging. Cancer Res 63(16):4960–4966PubMedGoogle Scholar
  47. 47.
    Yoshimatsu M, Toyokawa G, Hayami S, Unoki M, Tsunoda T, Field HI et al (2011) Dysregulation of PRMT1 and PRMT6, Type I arginine methyltransferases, is involved in various types of human cancers. Int J Cancer 128(3):562–573PubMedGoogle Scholar
  48. 48.
    Jeremy JY, Rowe D, Emsley AM, Newby AC (1999) Nitric oxide and the proliferation of vascular smooth muscle cells. Cardiovasc Res 43(3):580–594PubMedGoogle Scholar
  49. 49.
    Moncada S, Higgs EA (2006) Nitric oxide and the vascular endothelium. Handb Exp Pharmacol (176 Pt 1):213–254Google Scholar
  50. 50.
    Kang DH, Hughes J, Mazzali M, Schreiner GF, Johnson RJ (2001) Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol 12(7):1448–1457PubMedGoogle Scholar
  51. 51.
    Matsuguma K, Ueda S, Yamagishi S, Matsumoto Y, Kaneyuki U, Shibata R et al (2006) Molecular mechanism for elevation of asymmetric dimethylarginine and its role for hypertension in chronic kidney disease. J Am Soc Nephrol 17(8):2176–2183PubMedGoogle Scholar
  52. 52.
    Mihout F, Shweke N, Bige N, Jouanneau C, Dussaule JC, Ronco P et al (2011) Asymmetric dimethylarginine (ADMA) induces chronic kidney disease through a mechanism involving collagen and TGF-beta1 synthesis. J Pathol 223(1):37–45PubMedGoogle Scholar
  53. 53.
    Hadi HA, Suwaidi JA (2007) Endothelial dysfunction in diabetes mellitus. Vasc Health Risk Manag 3(6):853–876PubMedCentralPubMedGoogle Scholar
  54. 54.
    Tesfamariam B, Cohen RA (1992) Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol 263(2 Pt 2):H321–H326PubMedGoogle Scholar
  55. 55.
    Valkonen VP, Tuomainen TP, Laaksonen R (2005) DDAH gene and cardiovascular risk. Vasc Med 10(Suppl 1):S45–S48PubMedGoogle Scholar
  56. 56.
    Altinova AE, Arslan M, Sepici-Dincel A, Akturk M, Altan N, Toruner FB (2007) Uncomplicated type 1 diabetes is associated with increased asymmetric dimethylarginine concentrations. J Clin Endocrinol Metab 92(5):1881–1885PubMedGoogle Scholar
  57. 57.
    Tarnow L, Hovind P, Teerlink T, Stehouwer CD, Parving HH (2004) Elevated plasma asymmetric dimethylarginine as a marker of cardiovascular morbidity in early diabetic nephropathy in type 1 diabetes. Diabetes Care 27(3):765–769PubMedGoogle Scholar
  58. 58.
    Abhary S, Burdon KP, Kuot A, Javadiyan S, Whiting MJ, Kasmeridis N et al (2010) Sequence variation in DDAH1 and DDAH2 genes is strongly and additively associated with serum ADMA concentrations in individuals with type 2 diabetes. PLoS One 5(3):e9462PubMedCentralPubMedGoogle Scholar
  59. 59.
    Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M et al (2002) Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 106(8):987–992PubMedGoogle Scholar
  60. 60.
    Advani A, Gilbert RE (2012) The endothelium in diabetic nephropathy. Semin Nephrol 32(2):199–207PubMedGoogle Scholar
  61. 61.
    Hanai K, Babazono T, Nyumura I, Toya K, Tanaka N, Tanaka M et al (2009) Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes. Nephrol Dial Transplant 24(6):1884–1888PubMedGoogle Scholar
  62. 62.
    Marra M, Marchegiani F, Ceriello A, Sirolla C, Boemi M, Franceschi C et al (2013) Chronic renal impairment and DDAH2-1151 A/C polymorphism determine ADMA levels in type 2 diabetic subjects. Nephrol Dial Transplant 28(4):964–971PubMedGoogle Scholar
  63. 63.
    Ahn GO, Brown JM (2009) Role of endothelial progenitors and other bone marrow-derived cells in the development of the tumor vasculature. Angiogenesis 12(2):159–164PubMedCentralPubMedGoogle Scholar
  64. 64.
    Konishi H, Sydow K, Cooke JP (2007) Dimethylarginine dimethylaminohydrolase promotes endothelial repair after vascular injury. J Am Coll Cardiol 49(10):1099–1105PubMedGoogle Scholar
  65. 65.
    Schlager O, Giurgea A, Schuhfried O, Seidinger D, Hammer A, Groger M et al (2011) Exercise training increases endothelial progenitor cells and decreases asymmetric dimethylarginine in peripheral arterial disease: a randomized controlled trial. Atherosclerosis 217(1):240–248PubMedGoogle Scholar
  66. 66.
    Jiang DJ, Jia SJ, Dai Z, Li YJ (2006) Asymmetric dimethylarginine induces apoptosis via p38 MAPK/caspase-3-dependent signaling pathway in endothelial cells. J Mol Cell Cardiol 40(4):529–539PubMedGoogle Scholar
  67. 67.
    Pullamsetti SS, Savai R, Schaefer MB, Wilhelm J, Ghofrani HA, Weissmann N et al (2011) cAMP phosphodiesterase inhibitors increases nitric oxide production by modulating dimethylarginine dimethylaminohydrolases. Circulation 123(11):1194–1204PubMedGoogle Scholar
  68. 68.
    Chen YH, Xu X, Sheng MJ, Zheng Z, Gu Q (2011) Effects of asymmetric dimethylarginine on bovine retinal capillary endothelial cell proliferation, reactive oxygen species production, permeability, intercellular adhesion molecule-1, and occludin expression. Mol Vis 17:332–340PubMedGoogle Scholar
  69. 69.
    Sun Y, Zhou Q, Zhang W, Fu Y, Huang H (2002) ASYMMETRIC LEAVES1, an Arabidopsis gene that is involved in the control of cell differentiation in leaves. Planta 214(5):694–702PubMedGoogle Scholar
  70. 70.
    Li N, Worthmann H, Deb M, Chen S, Weissenborn K (2011) Nitric oxide (NO) and asymmetric dimethylarginine (ADMA): their pathophysiological role and involvement in intracerebral hemorrhage. Neurol Res 33(5):541–548PubMedGoogle Scholar
  71. 71.
    Jia SJ, Zhou Z, Zhang BK, Hu ZW, Deng HW, Li YJ (2009) Asymmetric dimethylarginine damages connexin43-mediated endothelial gap junction intercellular communication. Biochem Cell Biol 87(6):867–874PubMedGoogle Scholar
  72. 72.
    Gärtner C, Ziegelhoffer B, Kostelka M, Stepan H, Mohr FW, Dhein S (2012) Knock-down of endothelial connexins impairs angiogenesis. Pharmacol Res 65(3):347–357PubMedGoogle Scholar
  73. 73.
    Reaume AG, de Sousa PA, Kulkarni S, Langille BL, Zhu D, Davies TC et al (1995) Cardiac malformation in neonatal mice lacking connexin43. Science 267(5205):1831–1834PubMedGoogle Scholar
  74. 74.
    Simon AM, McWhorter AR (2002) Vascular abnormalities in mice lacking the endothelial gap junction proteins connexin37 and connexin40. Dev Biol 251(2):206–220PubMedGoogle Scholar
  75. 75.
    Giepmans BN (2004) Gap junctions and connexin-interacting proteins. Cardiovasc Res 62(2):233–245PubMedGoogle Scholar
  76. 76.
    Walker DL, Vacha SJ, Kirby ML, Lo CW (2005) Connexin43 deficiency causes dysregulation of coronary vasculogenesis. Dev Biol 284(2):479–498PubMedGoogle Scholar
  77. 77.
    Behrens J, Kameritsch P, Wallner S, Pohl U, Pogoda K (2010) The carboxyl tail of Cx43 augments p38 mediated cell migration in a gap junction-independent manner. Eur J Cell Biol 89(11):828–838PubMedGoogle Scholar
  78. 78.
    Fiedler LR, Wojciak-Stothard B (2009) The DDAH/ADMA pathway in the control of endothelial cell migration and angiogenesis. Biochem Soc Trans 37(Pt 6):1243–1247PubMedGoogle Scholar
  79. 79.
    Torondel B, Nandi M, Kelly P, Wojciak-Stothard B, Fleming I, Leiper J (2010) Adenoviral-mediated overexpression of DDAH improves vascular tone regulation. Vasc Med 15(3):205–213PubMedGoogle Scholar
  80. 80.
    Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279(5350):509–514PubMedGoogle Scholar
  81. 81.
    Loirand G, Guilluy C, Pacaud P (2006) Regulation of Rho proteins by phosphorylation in the cardiovascular system. Trends Cardiovasc Med 16(6):199–204PubMedGoogle Scholar
  82. 82.
    Storck EM, Wojciak-Stothard B (2013) Rho GTPases in pulmonary vascular dysfunction. Vascul Pharmacol 58(3):202–210PubMedGoogle Scholar
  83. 83.
    Ridley AJ (2001) Rho GTPases and cell migration. J Cell Sci 114(Pt 15):2713–2722PubMedGoogle Scholar
  84. 84.
    Sauzeau V, Rolli-Derkinderen M, Marionneau C, Loirand G, Pacaud P (2003) RhoA expression is controlled by nitric oxide through cGMP-dependent protein kinase activation. J Biol Chem 278(11):9472–9480PubMedGoogle Scholar
  85. 85.
    Schlegel N, Burger S, Golenhofen N, Walter U, Drenckhahn D, Waschke J (2008) The role of VASP in regulation of cAMP- and Rac 1-mediated endothelial barrier stabilization. Am J Physiol Cell Physiol 294(1):C178–C188PubMedGoogle Scholar
  86. 86.
    Comerford KM, Lawrence DW, Synnestvedt K, Levi BP, Colgan SP (2002) Role of vasodilator-stimulated phosphoprotein in PKA-induced changes in endothelial junctional permeability. FASEB J 16(6):583–585PubMedGoogle Scholar
  87. 87.
    Connolly JO, Simpson N, Hewlett L, Hall A (2002) Rac regulates endothelial morphogenesis and capillary assembly. Mol Biol Cell 13(7):2474–2485PubMedCentralPubMedGoogle Scholar
  88. 88.
    Sawada N, Salomone S, Kim HH, Kwiatkowski DJ, Liao JK (2008) Regulation of endothelial nitric oxide synthase and postnatal angiogenesis by Rac1. Circ Res 103(4):360–368PubMedCentralPubMedGoogle Scholar
  89. 89.
    Murohara T, Asahara T (2002) Nitric oxide and angiogenesis in cardiovascular disease. Antioxid Redox Signal 4(5):825–831PubMedGoogle Scholar
  90. 90.
    Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA et al (1995) Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377(6546):239–242PubMedGoogle Scholar
  91. 91.
    Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, O’Hara B, Rossiter S, Anthony S, Madhani M, Selwood D, Smith C, Wojciak-Stothard B, Rudiger A, Stidwill R, McDonald NQ, Vallance P (2007) Disruption of methylarginine metabolism impairs vascular homeostasis. Nat Med 13(2):198–203PubMedGoogle Scholar
  92. 92.
    Rikitake Y, Liao JK (2005) Rho GTPases, statins, and nitric oxide. Circ Res 97(12):1232–1235PubMedCentralPubMedGoogle Scholar
  93. 93.
    Rikitake Y, Liao JK (2005) Rho-kinase mediates hyperglycemia-induced plasminogen activator inhibitor-1 expression in vascular endothelial cells. Circulation 111(24):3261–3268PubMedCentralPubMedGoogle Scholar
  94. 94.
    Tokuo H, Yunoue S, Feng L, Kimoto M, Tsuji H, Ono T et al (2001) Phosphorylation of neurofibromin by cAMP-dependent protein kinase is regulated via a cellular association of N(G), N(G)-dimethylarginine dimethylaminohydrolase. FEBS Lett 494(1–2):48–53PubMedGoogle Scholar
  95. 95.
    Wu M, Wallace MR, Muir D (2006) Nf1 haploinsufficiency augments angiogenesis. Oncogene 25(16):2297–2303PubMedGoogle Scholar
  96. 96.
    Crowe DL (2004) Overlapping functions of Ras and Rac GTPases in regulating cancer cell proliferation and invasion. Anticancer Res 24(2B):593–597PubMedGoogle Scholar
  97. 97.
    Smith CL, Anthony S, Hubank M, Leiper JM, Vallance P (2005) Effects of ADMA upon gene expression: an insight into the pathophysiological significance of raised plasma ADMA. PLoS Med 2(10):e264PubMedCentralPubMedGoogle Scholar
  98. 98.
    Kingsley DM (1994) The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev 8(2):133–146PubMedGoogle Scholar
  99. 99.
    Mahmoud M, Upton PD, Arthur HM (2011) Angiogenesis regulation by TGFbeta signalling: clues from an inherited vascular disease. Biochem Soc Trans 39(6):1659–1666PubMedGoogle Scholar
  100. 100.
    Finkenzeller G, Hager S, Stark GB (2012) Effects of bone morphogenetic protein 2 on human umbilical vein endothelial cells. Microvasc Res 84(1):81–85PubMedGoogle Scholar
  101. 101.
    Morrell NW (2010) Role of bone morphogenetic protein receptors in the development of pulmonary arterial hypertension. Adv Exp Med Biol 661:251–264PubMedGoogle Scholar
  102. 102.
    Costa C, Incio J, Soares R (2007) Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis 10(3):149–166PubMedGoogle Scholar
  103. 103.
    Subramaniam A, Shanmugam MK, Perumal E, Li F, Nachiyappan A, Dai X et al (2013) Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma. Biochim Biophys Acta 1835(1):46–60PubMedGoogle Scholar
  104. 104.
    Mantovani A, Garlanda C, Allavena P (2010) Molecular pathways and targets in cancer-related inflammation. Ann Med 42(3):161–170PubMedGoogle Scholar
  105. 105.
    Kim YW, West XZ, Byzova TV (2013) Inflammation and oxidative stress in angiogenesis and vascular disease. J Mol Med (Berl) 91(3):323–328Google Scholar
  106. 106.
    Scott JA, North ML, Rafii M, Huang H, Pencharz P, Subbarao P et al (2011) Asymmetric dimethylarginine is increased in asthma. Am J Respir Crit Care Med 184(7):779–785PubMedGoogle Scholar
  107. 107.
    Kwaśny-Krochin B, Gluszko P, Undas A (2012) Plasma asymmetric dimethylarginine in active rheumatoid arthritis: links with oxidative stress and inflammation. Pol Arch Med Wewn 122(6):270–276PubMedGoogle Scholar
  108. 108.
    Tripepi G, Mattace Raso F, Sijbrands E, Seck MS, Maas R, Boger R et al (2011) Inflammation and asymmetric dimethylarginine for predicting death and cardiovascular events in ESRD patients. Clin J Am Soc Nephrol 6(7):1714–1721PubMedGoogle Scholar
  109. 109.
    van der Zwan LP, Scheffer PG, Dekker JM, Stehouwer CD, Heine RJ, Teerlink T (2011) Systemic inflammation is linked to low arginine and high ADMA plasma levels resulting in an unfavourable NOS substrate-to-inhibitor ratio: the Hoorn Study. Clin Sci (Lond) 121(2):71–78Google Scholar
  110. 110.
    Tanaka M, Sydow K, Gunawan F, Jacobi J, Tsao PS, Robbins RC, Cooke JP (2005) Dimethylargininedimethylaminohydrolase overexpression suppresses graft coronary artery disease. Circulation 112(11):1549–1556PubMedGoogle Scholar
  111. 111.
    Wei-Kang G, Dong-Liang Z, Xin-Xin W, Wei K, Zhang Y, Qi-Dong Z et al (2011) Actin cytoskeleton modulates ADMA-induced NF-kappaB nuclear translocation and ICAM-1 expression in endothelial cells. Med Sci Monit 17(9):BR242–BR247PubMedGoogle Scholar
  112. 112.
    Antoniades C, Shirodaria C, Leeson P, Antonopoulos A, Warrick N, Van-Assche T et al (2009) Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis. Eur Heart J 30(9):1142–1150PubMedGoogle Scholar
  113. 113.
    Schepers E, Barreto DV, Liabeuf S, Glorieux G, Eloot S, Barreto FC et al (2011) Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease. Clin J Am Soc Nephrol 6(10):2374–2383PubMedGoogle Scholar
  114. 114.
    Closs EI, Basha FZ, Habermeier A, Forstermann U (1997) Interference of L-arginine analogues with L-arginine transport mediated by the y + carrier hCAT-2B. Nitric Oxide 1(1):65–73PubMedGoogle Scholar
  115. 115.
    Bode-Böger SM, Scalera F, Kielstein JT, Martens-Lobenhoffer J, Breithardt G, Fobker M, Reinecke H (2006) Symmetrical dimethylarginine: a new combined parameter for renal function and extent of coronary artery disease. J Am Soc Nephrol 17(4):1128–1134PubMedGoogle Scholar
  116. 116.
    Cooke JP (2010) DDAH: a target for vascular therapy? Vasc Med 15(3):235–238PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  • Hilda Tsang
    • 1
  • Lucio Iannone
    • 1
  • Beata Wojciak-Stothard
    • 2
    Email author
  1. 1.Department of Experimental Medicine and ToxicologyHammersmith Campus, Imperial College LondonLondonUK
  2. 2.Department of Experimental Medicine and ToxicologyHammersmith Campus, Imperial College LondonLondonUK

Personalised recommendations