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Contrasting Roles of Different Endoglin Forms in Atherosclerosis

  • Jang, Young-Saeng (Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine) ;
  • Choi, In-Hong (Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine)
  • Received : 2014.09.05
  • Accepted : 2014.10.10
  • Published : 2014.10.31

Abstract

Endoglin (also known as CD105 or TGF-${\beta}$ type III receptor) is a co-receptor involved in TGF-${\beta}$ signaling. In atherosclerosis, TGF-${\beta}$ signaling is crucial in regulating disease progression owing to its anti-inflammatory effects as well as its inhibitory effects on smooth muscle cell proliferation and migration. Endoglin is a regulator of TGF-${\beta}$ signaling, but its role in atherosclerosis has yet to be defined. This review focuses on the roles of the various forms of endoglin in atherosclerosis. The expression of the two isoforms of endoglin (long-form and short-form) is increased in atherosclerotic lesions, and the expression of the soluble forms of endoglin is upregulated in sera of patients with hypercholesterolemia and atherosclerosis. Interestingly, long-form endoglin shows an atheroprotective effect via the induction of eNOS expression, while short-form and soluble endoglin enhance atherogenesis by inhibiting eNOS expression and TGF-${\beta}$ signaling. This review summarizes evidence suggesting that the different forms of endoglin have distinct roles in atherosclerosis.

Keywords

References

  1. Massague, J., and D. Wotton. 2000. Transcriptional control by the TGF-beta/Smad signaling system. EMBO J. 19: 1745-1754. https://doi.org/10.1093/emboj/19.8.1745
  2. Singh, N. N., and D. P. Ramji. 2006. The role of transforming growth factor-beta in atherosclerosis. Cytokine Growth Factor Rev. 17: 487-499. https://doi.org/10.1016/j.cytogfr.2006.09.002
  3. Mallat, Z., A. Gojova, C. Marchiol-Fournigault, B. Esposito, C. Kamate, R. Merval, D. Fradelizi, and A. Tedgui. 2001. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ. Res. 89: 930-934. https://doi.org/10.1161/hh2201.099415
  4. Feinberg, M. W., and M. K. Jain. 2005. Role of transforming growth factor-beta1/Smads in regulating vascular inflammation and atherogenesis. Panminerva Med. 47: 169-186.
  5. Lebrin, F., M. Deckers, P. Bertolino, and P. Ten Dijke. 2005. TGF-beta receptor function in the endothelium. Cardiovasc. Res. 65: 599-608. https://doi.org/10.1016/j.cardiores.2004.10.036
  6. Cheifetz, S., T. Bellon, C. Cales, S. Vera, C. Bernabeu, J. Massague, and M. Letarte. 1992. Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J. Biol. Chem. 267: 19027-19030.
  7. Gougos, A., and M. Letarte. 1990. Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J. Biol. Chem. 265: 8361-8364.
  8. Koleva, R. I., B. A. Conley, D. Romero, K. S. Riley, J. A. Marto, A. Lux, and C. P. Vary. 2006. Endoglin structure and function: Determinants of endoglin phosphorylation by transforming growth factor-beta receptors. J. Biol. Chem. 281: 25110-25123. https://doi.org/10.1074/jbc.M601288200
  9. Fernandez-Ruiz, E., S. St-Jacques, T. Bellon, M. Letarte, and C. Bernabeu. 1993. Assignment of the human endoglin gene (END) to 9q34${\rightarrow}$qter. Cytogenet. Cell Genet. 64: 204-207. https://doi.org/10.1159/000133576
  10. St-Jacques, S., U. Cymerman, N. Pece, and M. Letarte. 1994. Molecular characterization and in situ localization of murine endoglin reveal that it is a transforming growth factor-beta binding protein of endothelial and stromal cells. Endocrinology 134: 2645-2657. https://doi.org/10.1210/endo.134.6.8194490
  11. Bellon, T., A. Corbi, P. Lastres, C. Cales, M. Cebrian, S. Vera, S. Cheifetz, J. Massague, M. Letarte, and C. Bernabeu. 1993. Identification and expression of two forms of the human transforming growth factor-beta-binding protein endoglin with distinct cytoplasmic regions. Eur. J. Immunol. 23: 2340-2345. https://doi.org/10.1002/eji.1830230943
  12. Venkatesha, S., M. Toporsian, C. Lam, J. Hanai, T. Mammoto, Y. M. Kim, Y. Bdolah, K. H. Lim, H. T. Yuan, T. A. Libermann, I. E. Stillman, D. Roberts, P. A. D'Amore, F. H. Epstein, F. W. Sellke, R. Romero, V. P. Sukhatme, M. Letarte, and S. A. Karumanchi. 2006. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat. Med. 12: 642-649. https://doi.org/10.1038/nm1429
  13. Hawinkels, L. J., P. Kuiper, E. Wiercinska, H. W. Verspaget, Z. Liu, E. Pardali, C. F. Sier, and P. ten Dijke. 2010. Matrix metalloproteinase-14 (MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis. Cancer Res. 70: 4141-4150. https://doi.org/10.1158/0008-5472.CAN-09-4466
  14. Conley, B. A., J. D. Smith, M. Guerrero-Esteo, C. Bernabeu, and C. P. Vary. 2000. Endoglin, a TGF-beta receptor-associated protein, is expressed by smooth muscle cells in human atherosclerotic plaques. Atherosclerosis 153: 323-335. https://doi.org/10.1016/S0021-9150(00)00422-6
  15. Sanchez-Elsner, T., L. M. Botella, B. Velasco, C. Langa, and C. Bernabeu. 2002. Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways. J. Biol. Chem. 277: 43799-43808. https://doi.org/10.1074/jbc.M207160200
  16. Lastres, P., A. Letamendia, H. Zhang, C. Rius, N. Almendro, U. Raab, L. A. Lopez, C. Langa, A. Fabra, M. Letarte, and C. Bernabeu. 1996. Endoglin modulates cellular responses to TGF-beta 1. J. Cell Biol. 133: 1109-1121. https://doi.org/10.1083/jcb.133.5.1109
  17. Li, C., B. Guo, S. Ding, C. Rius, C. Langa, P. Kumar, C. Bernabeu, and S. Kumar. 2003. TNF alpha down-regulates CD105 expression in vascular endothelial cells: a comparative study with TGF beta 1. Anticancer Res. 23: 1189-1196.
  18. Ikemoto, T., Y. Hojo, H. Kondo, N. Takahashi, M. Hirose, Y. Nishimura, T. Katsuki, K. Shimada, and K. Kario. 2012. Plasma endoglin as a marker to predict cardiovascular events in patients with chronic coronary artery diseases. Heart Vessels 27: 344-351. https://doi.org/10.1007/s00380-011-0163-z
  19. Santibanez, J. F., M. Quintanilla, and C. Bernabeu. 2011. TGF-beta/TGF-beta receptor system and its role in physiological and pathological conditions. Clin. Sci. (Lond.) 121: 233-251. https://doi.org/10.1042/CS20110086
  20. Guerrero-Esteo, M., T. Sanchez-Elsner, A. Letamendia, and C. Bernabeu. 2002. Extracellular and cytoplasmic domains of endoglin interact with the transforming growth factor-beta receptors I and II. J. Biol. Chem. 277: 29197-29209. https://doi.org/10.1074/jbc.M111991200
  21. ten Dijke, P., M. J. Goumans, and E. Pardali. 2008. Endoglin in angiogenesis and vascular diseases. Angiogenesis 11: 79-89. https://doi.org/10.1007/s10456-008-9101-9
  22. Tian, F., A. X. Zhou, A. M. Smits, E. Larsson, M. J. Goumans, C. H. Heldin, J. Boren, and L. M. Akyurek. 2010. Endothelial cells are activated during hypoxia via endoglin/ALK-1/SMAD1/5 signaling in vivo and in vitro. Biochem. Biophys. Res. Commun. 392: 283-288. https://doi.org/10.1016/j.bbrc.2009.12.170
  23. Blanco, F. J., J. F. Santibanez, M. Guerrero-Esteo, C. Langa, C. P. Vary, and C. Bernabeu. 2005. Interaction and functional interplay between endoglin and ALK-1, two components of the endothelial transforming growth factor-beta receptor complex. J. Cell Physiol. 204: 574-584. https://doi.org/10.1002/jcp.20311
  24. Llorca, O., A. Trujillo, F. J. Blanco, and C. Bernabeu. 2007. Structural model of human endoglin, a transmembrane receptor responsible for hereditary hemorrhagic telangiectasia. J. Mol. Biol. 365: 694-705. https://doi.org/10.1016/j.jmb.2006.10.015
  25. Blanco, F. J., M. T. Grande, C. Langa, B. Oujo, S. Velasco, A. Rodriguez-Barbero, E. Perez-Gomez, M. Quintanilla, J. M. Lopez-Novoa, and C. Bernabeu. 2008. S-endoglin expression is induced in senescent endothelial cells and contributes to vascular pathology. Circ. Res. 103: 1383-1392. https://doi.org/10.1161/CIRCRESAHA.108.176552
  26. Gamble, J. R., Y. Khew-Goodall, and M. A. Vadas. 1993. Transforming growth factor-beta inhibits E-selectin expression on human endothelial cells. J. Immunol. 150: 4494-4503.
  27. Li, C., P. Mollahan, M. S. Baguneid, R. F. McMahon, P. Kumar, M. G. Walker, A. J. Freemont, and S. Kumar. 2006. A comparative study of neovascularisation in atherosclerotic plaques using CD31, CD105 and TGF beta 1. Pathobiology 73: 192-197. https://doi.org/10.1159/000096020
  28. Post, S., W. Peeters, E. Busser, D. Lamers, J. P. Sluijter, M. J. Goumans, R. A. de Weger, F. L. Moll, P. A. Doevendans, G. Pasterkamp, and A. Vink. 2008. Balance between angiopoietin-1 and angiopoietin-2 is in favor of angiopoietin-2 in atherosclerotic plaques with high microvessel density. J. Vasc. Res. 45: 244-250. https://doi.org/10.1159/000112939
  29. Blann, A. D., J. M. Wang, P. B. Wilson, and S. Kumar. 1996. Serum levels of the TGF-beta receptor are increased in atherosclerosis. Atherosclerosis 120: 221-226. https://doi.org/10.1016/0021-9150(95)05713-7
  30. Blazquez-Medela, A. M., L. Garcia-Ortiz, M. A. Gomez-Marcos, J. I. Recio-Rodriguez, A. Sanchez-Rodriguez, J. M. Lopez-Novoa, and C. Martinez-Salgado. 2010. Increased plasma soluble endoglin levels as an indicator of cardiovascular alterations in hypertensive and diabetic patients. BMC Med. 8: 86. https://doi.org/10.1186/1741-7015-8-86
  31. Li, C. G., H. Bethell, P. B. Wilson, D. Bhatnagar, M. G. Walker, and S. Kumar. 2000. The significance of CD105, TGFbeta and CD105/TGFbeta complexes in coronary artery disease. Atherosclerosis 152: 249-256. https://doi.org/10.1016/S0021-9150(99)00476-1

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