Stem Cell Reviews

, Volume 2, Issue 2, pp 93–101 | Cite as

Human umbilical vein endothelial cells and human dermal microvascular endothelial cells offer new insights into the relationship between lipid metabolism and angiogenesis

  • Ho-Jin Park
  • Yali Zhang
  • Serban P. Georgescu
  • Kristin L. Johnson
  • Dequon Kong
  • Jonas B. Galper

Abstract

Human umbilical vein endothelial cells (HUVECs) have played a major role as a model system for the study of the regulation of endothelial cell function and the role of the endothelium in the response of the blood vessel wall to stretch, shear forces, and the development of atherosclerotic plaques and angiogenesis. Here, we use HUVECs and human microvascular endothelial cells to study the role of the HMG-CoA reductase inhibitor, simvastatin, and the small GTP-binding protein Rho in the regulation of angiogenesis. Simvastatin inhibited angiogenesis in response to FGF-2 in the corneal pocket assay of the mouse and in vascular endothelial growth factor (VEGF)-stimulated angiogenesis in the chick chorioallontoic membrane. Furthermore, simvastatin inhibited VEGF-stimulated tube formation by human dermal microvascular endothelial cells and the formation of honeycomb-like structures by HUVECs. The effect was dose-dependent and was not secondary to apoptosis. Geranylgeranyl-pyrophosphate (GGPP), a product of the cholesterol metabolic pathway that serves as a substrate for the posttranslational lipidation of RhoA, was required for membrane localization, but not farnesylpyrophosphate (FPP), the substrate for the lipidation of Ras. Furthermore, GGTI, a specific inhibitor of GGPP, mimicked the effect of simvastatin of tube formation and the formation of honeycombs whereas FTI, a specific inhibitor of the farnesylation of Ras, had no effect. Adenoviral expression of a DN-RhoA mutant mimicked the effect of simvastatin on tube formation and the formation of honeycombs, whereas a dominant activating mutant of RhoA reversed the effect of simvastatin on tube formation. Finally, simvastatin interfered with the membrane localization of RhoA with a dose-dependence similar to that for the inhibition of tube formation. Simvastatin also inhibited the VEGF-stimulated phosphorylation of the VEGF receptor KDR, and the tyrosine kinase FAK, which plays a role in cell migration. These data demonstrate that simvastatin interfered with angiogenesis via the inhibition of RhoA. Data supporting a role for angiogenesis in the development and growth of atherosclerotic plaques suggest that this antiangiogenic effect of Statins might prevent the progression of atherosclerosis via the inhibition of plaque angiogenesis.

Index Entries

Human umbilical vein endothelial cells human dermal microvascular endothelial cells angiogenesis HMG-CoA reductase inhibitors simvastatin RhoA 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Yamada T, Fan J, Shimokama T, Tokunaga O, Watanabe T. Am J Pathol 1992;241(6):1435–1444.Google Scholar
  2. 2.
    Bevilacqua MP, Gimbrone MA, Jr. 1987;13(4):425–433.Google Scholar
  3. 3.
    Libby P. J Intern Med 2000;247(3):349–358.PubMedCrossRefGoogle Scholar
  4. 4.
    Davies PF. J Vasc Res 1997;34(3):208–211.PubMedGoogle Scholar
  5. 5.
    Gimbrone MA, Jr. Prog Hemost Thromb 1976;3:1–28.PubMedGoogle Scholar
  6. 6.
    Goldberger A, Middleton KA, Oliver JA, et al. J Biol Chem 1994; 269(25):17,183–17,191.Google Scholar
  7. 7.
    Namiki A, Brogi E, Kearney M, et al. J Biol Chem 1995;270 (52):31,189–31,195.Google Scholar
  8. 8.
    Nozawa F, Hirota M, Okabe A, et al. Pancreas 2000;21(4):392–398.PubMedCrossRefGoogle Scholar
  9. 9.
    Muscella A, Marsigliante S, Carluccio MA, Vinson GP, Storelli C, et al. J Endocrinol 1997;155(3):587–593.PubMedCrossRefGoogle Scholar
  10. 10.
    Burns MP, DePaola N. Am J Physiol Heart Circ Physiol 2005; 288(1):H194-H204.PubMedCrossRefGoogle Scholar
  11. 11.
    Kokura S, Wolf RE, Yoshikawa T, Granger DN, Aw TY. Circ Res 1999;84(5):516–524.PubMedGoogle Scholar
  12. 12.
    Zhang W, DeMattia JA, Song H, Couldwell WT. J Neurosurg 2003;98(4):846–853.PubMedCrossRefGoogle Scholar
  13. 13.
    Bevilacqua MP, Stengelin S, Gimbrone MA, Jr, Seed B, et al. Science 1989;243(4895):1160–1165.PubMedCrossRefGoogle Scholar
  14. 14.
    Parmar KM, Larman HB, Dai G, et al. J Clin Invest 2006; 116(1):49–58.PubMedCrossRefGoogle Scholar
  15. 15.
    Parmar KM, Nambudiri V, Dai G, Larman HB, et al. J Biol Chem. 2005;280(29):26,714–26,719.CrossRefGoogle Scholar
  16. 16.
    Dai G, Kaazempur-Mofrad MR, Natarajan S, et al. Proc Natl Acad Sci USA 2004;101(41):14,871–14,876.CrossRefGoogle Scholar
  17. 17.
    Kumar S, Li C. Trends Immunol 2001;22(3):129.PubMedCrossRefGoogle Scholar
  18. 18.
    Yoon YS, Johnson IA, Park JS, Diaz L, Losordo DW. Mol Cell Biochem 2004;264(1–2):63–74.PubMedCrossRefGoogle Scholar
  19. 19.
    Nagata D, Mogi M, Walsh K. J Biol Chem 2003;278(33):31,000–31,006.CrossRefGoogle Scholar
  20. 20.
    Park HJ, Kong D, Iruela-Arispe L, Begley U, Tang D, Galper JB. Circ Res 2002;91(2):143–150.PubMedCrossRefGoogle Scholar
  21. 21.
    Weis M, Heeschen C, Glassford AJ, Cooke JP. Circulation 2002;105(6):739–745.PubMedCrossRefGoogle Scholar
  22. 22.
    Goldstein JL, Brown MS. Nature 1990;343(6257):425–430.PubMedCrossRefGoogle Scholar
  23. 23.
    Grundy SM. Circulation 1998;97(15):1436–1439.PubMedGoogle Scholar
  24. 24.
    Massy ZA, Keane WF, Kasiske BL. Lancet 1996;347(8994):102–103.PubMedCrossRefGoogle Scholar
  25. 25.
    Sacks FM, Moye LA, Davis BR, et al. Circulation 1998;97(15):1446–1452.PubMedGoogle Scholar
  26. 26.
    Laufs U, La Fata V, Plutzky J, Liao JK. Circulation 1998;97(12):1129–1135.PubMedGoogle Scholar
  27. 27.
    Lerner EC, Qian Y, Blaskovich MA, et al. J Biol Chem 1995;270(45):26,802–26,806.Google Scholar
  28. 28.
    Vogt A, Qian Y, McGuire TF, Hamilton AD, Sebti SM. Oncogene 1996;13(9):1991–1999.PubMedGoogle Scholar
  29. 29.
    Ernst JD. Cell Microbiol 2000;2(5):379–386.PubMedCrossRefGoogle Scholar
  30. 30.
    Gossen M, Bujard H. Proc Natl Acad Sci USA 1992;89(12):5547–5551.PubMedCrossRefGoogle Scholar
  31. 31.
    Gingras D, Lamy S, Beliveau R. Biochem J 2000;348(Part 2):273–280.PubMedCrossRefGoogle Scholar
  32. 32.
    Clark EA, King WG, Brugge JS, Symons M, Hynes RO. J Cell Biol 1998;142(2):573–586.PubMedCrossRefGoogle Scholar
  33. 33.
    Robert P, Tsui P, Laville MP, et al. J Mol Cell Cardiol 2001; 33(9):1589–1606.PubMedCrossRefGoogle Scholar
  34. 34.
    Urbich C, Dernbach E, Zeiher AM, Dimmeler S. Circ Res 2002;90(6):737–744.PubMedCrossRefGoogle Scholar
  35. 35.
    Feleszko W, Balkowiec EZ, Sieberth E, et al. Int J Cancer 1999;81(4):560–567.PubMedCrossRefGoogle Scholar
  36. 36.
    Vincent L, Chen W, Hong L, et al. FEBS Lett 2001;495(3):159–166.PubMedCrossRefGoogle Scholar
  37. 37.
    Williams JK, Sukhova GK, Herrington DM, Libby P. J Am Coll Cardiol 1998;31(3):684–691.PubMedCrossRefGoogle Scholar
  38. 38.
    Wilson SH, Herrmann J, Lerman LO, et al. Circulation 2002;105(4):415–418.PubMedCrossRefGoogle Scholar
  39. 39.
    Gordon B, Chang S, Kavanagh M, et al. Am J Ophthalmol 1991;112(4):385–391.PubMedGoogle Scholar
  40. 40.
    Folkman J. Nat Med 1995;1(1):27–31.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2006

Authors and Affiliations

  • Ho-Jin Park
    • 1
  • Yali Zhang
    • 1
  • Serban P. Georgescu
    • 1
  • Kristin L. Johnson
    • 1
  • Dequon Kong
    • 1
  • Jonas B. Galper
    • 1
  1. 1.Molecular Cardiology Research Institute, Cardiology Division, Department of MedicineTufts New England Medical CenterBoston

Personalised recommendations