Immune Netw.  2014 Oct;14(5):237-240. 10.4110/in.2014.14.5.237.

Contrasting Roles of Different Endoglin Forms in Atherosclerosis

Affiliations
  • 1Department of Microbiology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 120-749, Korea. inhong@yuhs.ac

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.

Keyword

Endoglin; Atherosclerosis; TGF-beta; Smad

MeSH Terms

Atherosclerosis*
Disease Progression
Humans
Hypercholesterolemia
Myocytes, Smooth Muscle
Protein Isoforms
Transforming Growth Factor beta
Protein Isoforms
Transforming Growth Factor beta

Reference

1. Massague J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. EMBO J. 2000; 19:1745–1754.
2. Singh NN, Ramji DP. The role of transforming growth factor-beta in atherosclerosis. Cytokine Growth Factor Rev. 2006; 17:487–499.
3. Mallat Z, Gojova A, Marchiol-Fournigault C, Esposito B, Kamate C, Merval R, Fradelizi D, Tedgui A. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res. 2001; 89:930–934.
Article
4. Feinberg MW, Jain MK. Role of transforming growth factor-beta1/Smads in regulating vascular inflammation and atherogenesis. Panminerva Med. 2005; 47:169–186.
5. Lebrin F, Deckers M, Bertolino P, Ten Dijke P. TGF-beta receptor function in the endothelium. Cardiovasc Res. 2005; 65:599–608.
6. Cheifetz S, Bellon T, Cales C, Vera S, Bernabeu C, Massague J, Letarte M. Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J Biol Chem. 1992; 267:19027–19030.
Article
7. Gougos A, Letarte M. Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem. 1990; 265:8361–8364.
Article
8. Koleva RI, Conley BA, Romero D, Riley KS, Marto JA, Lux A, Vary CP. Endoglin structure and function: Determinants of endoglin phosphorylation by transforming growth factor-beta receptors. J Biol Chem. 2006; 281:25110–25123.
9. Fernandez-Ruiz E, St-Jacques S, Bellon T, Letarte M, Bernabeu C. Assignment of the human endoglin gene (END) to 9q34→qter. Cytogenet Cell Genet. 1993; 64:204–207.
Article
10. St-Jacques S, Cymerman U, Pece N, Letarte M. 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. 1994; 134:2645–2657.
Article
11. Bellon T, Corbi A, Lastres P, Cales C, Cebrian M, Vera S, Cheifetz S, Massague J, Letarte M, Bernabeu C. Identification and expression of two forms of the human transforming growth factor-beta-binding protein endoglin with distinct cytoplasmic regions. Eur J Immunol. 1993; 23:2340–2345.
12. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D'Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006; 12:642–649.
Article
13. Hawinkels LJ, Kuiper P, Wiercinska E, Verspaget HW, Liu Z, Pardali E, Sier CF, ten Dijke P. Matrix metalloproteinase-14 (MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis. Cancer Res. 2010; 70:4141–4150.
Article
14. Conley BA, Smith JD, Guerrero-Esteo M, Bernabeu C, Vary CP. Endoglin, a TGF-beta receptor-associated protein, is expressed by smooth muscle cells in human atherosclerotic plaques. Atherosclerosis. 2000; 153:323–335.
Article
15. Sanchez-Elsner T, Botella LM, Velasco B, Langa C, Bernabeu C. Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways. J Biol Chem. 2002; 277:43799–43808.
16. Lastres P, Letamendia A, Zhang H, Rius C, Almendro N, Raab U, Lopez LA, Langa C, Fabra A, Letarte M, Bernabeu C. Endoglin modulates cellular responses to TGF-beta 1. J Cell Biol. 1996; 133:1109–1121.
Article
17. Li C, Guo B, Ding S, Rius C, Langa C, Kumar P, Bernabeu C, Kumar S. TNF alpha down-egulates CD105 expression in vascular endothelial cells: a comparative study with TGF beta 1. Anticancer Res. 2003; 23:1189–1196.
18. Ikemoto T, Hojo Y, Kondo H, Takahashi N, Hirose M, Nishimura Y, Katsuki T, Shimada K, Kario K. Plasma endoglin as a marker to predict cardiovascular events in patients with chronic coronary artery diseases. Heart Vessels. 2012; 27:344–351.
Article
19. Santibanez JF, Quintanilla M, Bernabeu C. TGF-beta/TGF-beta receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 2011; 121:233–251.
20. Guerrero-Esteo M, Sanchez-Elsner T, Letamendia A, Bernabeu C. Extracellular and cytoplasmic domains of endoglin interact with the transforming growth factor-beta receptors I and II. J Biol Chem. 2002; 277:29197–29209.
Article
21. ten Dijke P, Goumans MJ, Pardali E. Endoglin in angiogenesis and vascular diseases. Angiogenesis. 2008; 11:79–89.
Article
22. Tian F, Zhou AX, Smits AM, Larsson E, Goumans MJ, Heldin CH, Boren J, Akyurek LM. Endothelial cells are activated during hypoxia via endoglin/ALK-1/SMAD1/5 signaling in vivo and in vitro. Biochem Biophys Res Commun. 2010; 392:283–288.
Article
23. Blanco FJ, Santibanez JF, Guerrero-Esteo M, Langa C, Vary CP, Bernabeu C. Interaction and functional interplay between endoglin and ALK-1, two components of the endothelial transforming growth factor-beta receptor complex. J Cell Physiol. 2005; 204:574–584.
Article
24. Llorca O, Trujillo A, Blanco FJ, Bernabeu C. Structural model of human endoglin, a transmembrane receptor responsible for hereditary hemorrhagic telangiectasia. J Mol Biol. 2007; 365:694–705.
Article
25. Blanco FJ, Grande MT, Langa C, Oujo B, Velasco S, Rodriguez-Barbero A, Perez-Gomez E, Quintanilla M, Lopez-Novoa JM, Bernabeu C. S-endoglin expression is induced in senescent endothelial cells and contributes to vascular pathology. Circ Res. 2008; 103:1383–1392.
Article
26. Gamble JR, Khew-Goodall Y, Vadas MA. Transforming growth factor-beta inhibits E-selectin expression on human endothelial cells. J Immunol. 1993; 150:4494–4503.
27. Li C, Mollahan P, Baguneid MS, McMahon RF, Kumar P, Walker MG, Freemont AJ, Kumar S. A comparative study of neovascularisation in atherosclerotic plaques using CD31, CD105 and TGF beta 1. Pathobiology. 2006; 73:192–197.
Article
28. Post S, Peeters W, Busser E, Lamers D, Sluijter JP, Goumans MJ, de Weger RA, Moll FL, Doevendans PA, Pasterkamp G, Vink A. Balance between angiopoietin-1 and angiopoietin-2 is in favor of angiopoietin-2 in atherosclerotic plaques with high microvessel density. J Vasc Res. 2008; 45:244–250.
Article
29. Blann AD, Wang JM, Wilson PB, Kumar S. Serum levels of the TGF-beta receptor are increased in atherosclerosis. Atherosclerosis. 1996; 120:221–226.
Article
30. Blazquez-Medela AM, Garcia-Ortiz L, Gomez-Marcos MA, Recio-Rodriguez JI, Sanchez-Rodriguez A, Lopez-Novoa JM, Martinez-Salgado C. Increased plasma soluble endoglin levels as an indicator of cardiovascular alterations in hypertensive and diabetic patients. BMC Med. 2010; 8:86.
Article
31. Li CG, Bethell H, Wilson PB, Bhatnagar D, Walker MG, Kumar S. The significance of CD105, TGFbeta and CD105/TGFbeta complexes in coronary artery disease. Atherosclerosis. 2000; 152:249–256.
Article
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