Krüppel-like Factors in the Vascular Endothelium

  • Guillermo García-Cardeña
  • Guadalupe Villarreal


Although Krüppel-like factors (KLFs) have been the subject of extensive biological investigation, the role of this family of transcription factors in the biology and pathophysiology of the vascular endothelium is just becoming apparent. Most investigative efforts thus far have focused on KLF2, its contribution to the endothelial vasoprotective phenotype, and its possible impact on atherogenesis. This chapter reflects on the current state of the field and highlights evolving areas where KLFs are emerging as important regulators of endothelial function.


Human Umbilical Vein Endothelial Cell Fluid Shear Stress KLF2 Expression Smooth Muscle Cell Migration Laminar Shear Stress 
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  1. Anderson KP, Kern CB, Crable SC, and Lingrel JB (1995) Isolation of a gene encoding a functional zinc finger protein homologous to erythroid Kruppel-like factor: identification of a new multigene family. Mol Cell Biol 15, 5957–5965.PubMedGoogle Scholar
  2. Atkins GB, Wang Y, Mahabeleshwar GH, Shi H, Gao H, Kawanami D, Natesan V, Lin Z, Simon DI, and Jain MK (2008) Hemizygous deficiency of Kruppel-like factor 2 augments experimental atherosclerosis. Circ Res 103, 690–693.PubMedCrossRefGoogle Scholar
  3. Bhattacharya R, Senbanerjee S, Lin Z, Mir S, Hamik A, Wang P, Mukherjee P, Mukhopadhyay D, and Jain MK (2005) Inhibition of vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis by the Kruppel-like factor KLF2. J Biol Chem 280, 28848–28851.PubMedCrossRefGoogle Scholar
  4. Bi W, Drake CJ, and Schwarz JJ (1999) The transcription factor MEF2C-null mouse exhibits complex vascular malformations and reduced cardiac expression of angiopoietin 1 and VEGF. Dev Biol 211, 255–267.PubMedCrossRefGoogle Scholar
  5. Bieker JJ (2001) Kruppel-like factors: three fingers in many pies. J Biol Chem 276, 34355–34358.PubMedCrossRefGoogle Scholar
  6. Botella LM, Sanchez-Elsner T, Sanz-Rodriguez F, Kojima S, Shimada J, Guerrero-Esteo M, Cooreman MP, Ratziu V, Langa C, Vary CP et al (2002) Transcriptional activation of endoglin and transforming growth factor-beta signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury. Blood 100, 4001–4010.PubMedCrossRefGoogle Scholar
  7. Brindle NP, Saharinen P, and Alitalo K (2006) Signaling and functions of angiopoietin-1 in vascular protection. Circ Res 98, 1014–1023.PubMedCrossRefGoogle Scholar
  8. Cao S, Fernandez-Zapico ME, Jin D, Puri V, Cook TA, Lerman LO, Zhu X Y, Urrutia R, and Shah V (2005) KLF11-mediated repression antagonizes Sp1/sterol-responsive element-binding protein-induced transcriptional activation of caveolin-1 in response to cholesterol signaling. J Biol Chem 280, 1901–1910.PubMedCrossRefGoogle Scholar
  9. Conkright MD, Wani MA, and Lingrel JB (2001) Lung Kruppel-like factor contains an autoinhibi-tory domain that regulates its transcriptional activation by binding WWP1, an E3 ubiquitin ligase. J Biol Chem 276, 29299–29306.PubMedCrossRefGoogle Scholar
  10. Dai G, Kaazempur-Mofrad MR, Natarajan S, Zhang Y, Vaughn S, Blackman BR, Kamm RD, Garcia-Cardena G, and Gimbrone MA Jr (2004) Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature. Proc Natl Acad Sci U S A 101, 14871–14876.PubMedCrossRefGoogle Scholar
  11. Das A, Fernandez-Zapico ME, Cao S, Yao J, Fiorucci S, Hebbel RP, Urrutia R, and Shah VH (2006) Disruption of an SP2/KLF6 repression complex by SHP is required for farnesoid X receptor-induced endothelial cell migration. J Biol Chem 281, 39105–39113.PubMedCrossRefGoogle Scholar
  12. Dekker RJ, van Soest S, Fontijn RD, Salamanca S, de Groot PG, VanBavel E, Pannekoek H, and Horrevoets AJ (2002) Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Kruppel-like factor (KLF2). Blood 100, 1689–1698.PubMedCrossRefGoogle Scholar
  13. Dekker RJ, van Thienen JV, Rohlena J, de Jager SC, Elderkamp YW, Seppen J, de Vries CJ, Biessen EA, van Berkel TJ, Pannekoek H, and Horrevoets AJ (2005) Endothelial KLF2 links local arterial shear stress levels to the expression of vascular tone-regulating genes. Am J Pathol 167, 609–618.PubMedGoogle Scholar
  14. Fukuhara S, Sako K, Minami T, Noda K, Kim HZ, Kodama T, Shibuya M, Takakura N, Koh GY, and Mochizuki N (2008) Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nat Cell Biol 10, 513–526.PubMedCrossRefGoogle Scholar
  15. Hamik A, Lin Z, Kumar A, Balcells M, Sinha S, Katz J, Feinberg MW, Gerzsten RE, Edelman ER, and Jain MK (2007) Kruppel-like factor 4 regulates endothelial inflammation. J Biol Chem 282, 13769–13779.PubMedCrossRefGoogle Scholar
  16. Homeister JW, and Patterson C (2008) Zinc fingers in the pizza pie aorta. Circ Res 103, 687–689.PubMedCrossRefGoogle Scholar
  17. Huddleson JP, Srinivasan S, Ahmad N, and Lingrel JB (2004) Fluid shear stress induces endothe-lial KLF2 gene expression through a defined promoter region. Biol Chem 385, 723–729.PubMedCrossRefGoogle Scholar
  18. Jiang J, Chan YS, Loh YH, Cai J, Tong GQ, Lim CA, Robson P, Zhong S, and Ng HH (2008) A core Klf circuitry regulates self-renewal of embryonic stem cells. Nat Cell Biol 10, 353–360.PubMedCrossRefGoogle Scholar
  19. Kinderlerer AR, Ali F, Johns M, Lidington EA, Leung V, Boyle JJ, Hamdulay SS, Evans PC, Haskard DO, and Mason JC (2008) KLF2-dependent, shear stress-induced expression of CD59: a novel cytoprotective mechanism against complement-Google Scholar
  20. Kojima S, Hayashi S, Shimokado K, Suzuki Y, Shimada J, Crippa MP, and Friedman SL (2000) Transcriptional activation of urokinase by the Kruppel-like factor Zf9/COPEB activates latent TGF-beta1 in vascular endothelial cells. Blood 95, 1309–1316.PubMedGoogle Scholar
  21. Kumar A, Lin Z, SenBanerjee S, and Jain MK (2005) Tumor necrosis factor alpha-mediated reduction of KLF2 is due to inhibition of MEF2 by NF-kappaB and histone deacetylases. Mol Cell Biol 25, 5893–5903.PubMedCrossRefGoogle Scholar
  22. Kuo CT, Veselits ML, Barton KP, Lu MM, Clendenin C, and Leiden JM (1997) The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilization during murine embryogenesis. Genes Dev 11, 2996–3006.PubMedCrossRefGoogle Scholar
  23. Lee JS, Yu Q, Shin JT, Sebzda E, Bertozzi C, Chen M, Mericko P, Stadtfeld M, Zhou D, Cheng L et al (2006) Klf2 is an essential regulator of vascular hemodynamic forces in vivo. Dev Cell 11, 845–857.PubMedCrossRefGoogle Scholar
  24. Liao JK, and Laufs U (2005) Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 45, 89–118.PubMedCrossRefGoogle Scholar
  25. Lin Z, Kumar A, SenBanerjee S, Staniszewski K, Parmar K, Vaughan DE, Gimbrone MA Jr, Balasubramanian V, Garcia-Cardena G, and Jain MK (2005) Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circ Res 96, e48–57.PubMedCrossRefGoogle Scholar
  26. Mack PJ, Zhang Y, Chung S, Vickerman V, Kamm RD, and Garcia-Cardena G (2008) Biomechanical regulation of endothelial-dependent events critical for adaptive remodeling. J Biol Chem.Google Scholar
  27. Makowski L, Boord JB, Maeda K, Babaev VR, Uysal KT, Morgan MA, Parker RA, Suttles J, Fazio S, Hotamisligil GS, and Linton MF (2001) Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med 7, 699–705.PubMedCrossRefGoogle Scholar
  28. McCormick SM, Eskin SG, McIntire LV, Teng CL, Lu CM, Russell CG, and Chittur KK (2001) DNA microarray reveals changes in gene expression of shear stressed human umbilical vein endothelial cells. Proc Natl Acad Sci U S A 98, 8955–8960.PubMedCrossRefGoogle Scholar
  29. Methe H, Balcells M, Alegret Mdel C, Santacana M, Molins B, Hamik A, Jain MK, and Edelman ER (2007) Vascular bed origin dictates flow pattern regulation of endothelial adhesion molecule expression. Am J Physiol Heart Circ Physiol 292, H2167–2175.PubMedCrossRefGoogle Scholar
  30. Nusslein-Volhard C, and Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287, 795–801.PubMedCrossRefGoogle Scholar
  31. Oates AC, Pratt SJ, Vail B, Yan Y, Ho RK, Johnson SL, Postlethwait JH, and Zon LI (2001) The zebrafish klf gene family. Blood 98, 792–801.CrossRefGoogle Scholar
  32. Parmar KM, Larman HB, Dai G, Zhang Y, Wang ET, Moorthy SN, Kratz JR, Lin Z, Jain MK, Gimbrone MA Jr, and Garcia-Cardena G (2006) Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J Clin Invest 116, 49–58.PubMedCrossRefGoogle Scholar
  33. Parmar KM, Nambudiri V, Dai G, Larman HB, Gimbrone MA Jr, and Garcia-Cardena G (2005) Statins exert endothelial atheroprotective effects via the KLF2 transcription factor. J Biol Chem 280, 26714–26719.PubMedCrossRefGoogle Scholar
  34. Sako K, Fukuhara S, Minami T, Hamakubo T, Song H, Kodama T, Fukamizu A, Gutkind JS, Koh G Y, and Mochizuki N (2008) Angiopoietin-1 induces Kruppel-like factor 2 expression through a phosphoinositide 3-kinase/AKT-dependent activation of myocyte enhancer factor 2. J Biol Chem.Google Scholar
  35. Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, Gridley T, Wolburg H, Risau W, and Qin Y (1995) Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376, 70–74.PubMedCrossRefGoogle Scholar
  36. Sauer F, and Jackle H (1993) Dimerization and the control of transcription by Kruppel. Nature 364, 454–457.PubMedCrossRefGoogle Scholar
  37. Segre JA, Bauer C, and Fuchs E (1999) Klf4 is a transcription factor required for establishing the barrier function of the skin. Nat Genet 22, 356–360.PubMedCrossRefGoogle Scholar
  38. SenBanerjee S, Lin Z, Atkins GB, Greif DM, Rao RM, Kumar A, Feinberg MW, Chen Z, Simon DI, Luscinskas FW et al (2004) KLF2 Is a novel transcriptional regulator of endothelial proin-flammatory activation. J Exp Med 199, 1305–1315.PubMedCrossRefGoogle Scholar
  39. Sen-Banerjee S, Mir S, Lin Z, Hamik A, Atkins GB, Das H, Banerjee P, Kumar A, and Jain MK (2005) Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells. Circulation 112, 720–726.PubMedCrossRefGoogle Scholar
  40. Suske G, Bruford E, and Philipsen S (2005) Mammalian SP/KLF transcription factors: bring in the family. Genomics 85, 551–556.PubMedCrossRefGoogle Scholar
  41. Wang F, Zhu Y, Huang Y, McAvoy S, Johnson WB, Cheung TH, Chung TK, Lo KW, Yim SF, Yu MM et al (2005) Transcriptional repression of WEE1 by Kruppel-like factor 2 is involved in DNA damage-induced apoptosis. Oncogene 24, 3875–3885.PubMedCrossRefGoogle Scholar
  42. Wang L, Fan C, Topol SE, Topol EJ, and Wang Q (2003) Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science 302, 1578–1581.PubMedCrossRefGoogle Scholar
  43. Wani MA, Conkright MD, Jeffries S, Hughes MJ, and Lingrel JB (1999) cDNA isolation, genomic structure, regulation, and chromosomal localization of human lung Kruppel-like factor. Genomics 60, 78–86.PubMedCrossRefGoogle Scholar
  44. Weng L, Kavaslar N, Ustaszewska A, Doelle H, Schackwitz W, Hebert S, Cohen JC, McPherson R, and Pennacchio LA (2005) Lack of MEF2A mutations in coronary artery disease. J Clin Invest 115, 1016–1020.PubMedGoogle Scholar
  45. Wong AL, Haroon ZA, Werner S, Dewhirst MW, Greenberg CS, and Peters KG (1997) Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ Res 81, 567–574.PubMedGoogle Scholar
  46. Wu J, Bohanan CS, Neumann JC, and Lingrel JB (2008) KLF2 transcription factor modulates blood vessel maturation through smooth muscle cell migration. J Biol Chem 283, 3942–3950.PubMedCrossRefGoogle Scholar
  47. Yet SF, McA'Nulty MM, Folta SC, Yen HW, Yoshizumi M, Hsieh CM, Layne MD, Chin MT, Wang H, Perrella MA et al (1998) Human EZF, a Kruppel-like zinc finger protein, is expressed in vascular endothelial cells and contains transcriptional activation and repression domains. J Biol Chem 273, 1026–1031.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Guillermo García-Cardeña
    • 1
  • Guadalupe Villarreal
    • 1
    • 2
  1. 1.Laboratory for Systems Biology, Center for Excellence in Vascular Biology, Departments of PathologyHarvard Medical School and Brigham and Women's HospitalBostonUSA
  2. 2.Harvard-MIT Division of HealthSciences and TechnologyBostonUSA

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