Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2001 Nov 1;359(Pt 3):567–574. doi: 10.1042/0264-6021:3590567

Albumin-derived advanced glycation end-products trigger the disruption of the vascular endothelial cadherin complex in cultured human and murine endothelial cells.

K Otero 1, F Martínez 1, A Beltrán 1, D González 1, B Herrera 1, G Quintero 1, R Delgado 1, A Rojas 1
PMCID: PMC1222177  PMID: 11672430

Abstract

Endothelial cell (EC) junctions regulate in large part the integrity and barrier function of the vascular endothelium. Advanced glycation end-products (AGEs), the irreversibly formed reactive derivatives of non-enzymic glucose-protein condensation reactions, are strongly implicated in endothelial dysfunction that distinguishes diabetes- and aging-associated vascular complications. The aim of the present study was to determine whether AGEs affect EC lateral junction proteins, with particular regard to the vascular endothelial cadherin (VE-cadherin) complex. Our results indicate that AGE-modified BSA (AGE-BSA), a prototype of advanced glycated proteins, disrupts the VE-cadherin complex when administered to ECs. AGE-BSA, but not unmodified BSA, was found to induce decreases in the levels of VE-cadherin, beta-catenin and gamma-catenin in the complex and in total cell extracts, as well as a marked reduction in the amount of VE-cadherin present at the cell surface. In contrast, the level of platelet endothelial cell adhesion molecule-1 (PECAM-1), which is located at lateral junctions, was not altered. Supplementation of the cellular antioxidative defences abolished these effects. Finally, the loss of components of the VE-cadherin complex was correlated with increases in vascular permeability and in EC migration. These findings suggest that some of the AGE-induced biological effects on the endothelium could be mediated, at least in part, by the weakening of intercellular contacts caused by decreases in the amount of VE-cadherin present.

Full Text

The Full Text of this article is available as a PDF (246.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bach T. L., Barsigian C., Chalupowicz D. G., Busler D., Yaen C. H., Grant D. S., Martinez J. VE-Cadherin mediates endothelial cell capillary tube formation in fibrin and collagen gels. Exp Cell Res. 1998 Feb 1;238(2):324–334. doi: 10.1006/excr.1997.3844. [DOI] [PubMed] [Google Scholar]
  2. Berman M. E., Muller W. A. Ligation of platelet/endothelial cell adhesion molecule 1 (PECAM-1/CD31) on monocytes and neutrophils increases binding capacity of leukocyte CR3 (CD11b/CD18). J Immunol. 1995 Jan 1;154(1):299–307. [PubMed] [Google Scholar]
  3. Bierhaus A., Chevion S., Chevion M., Hofmann M., Quehenberger P., Illmer T., Luther T., Berentshtein E., Tritschler H., Müller M. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes. 1997 Sep;46(9):1481–1490. doi: 10.2337/diab.46.9.1481. [DOI] [PubMed] [Google Scholar]
  4. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  5. Brett J., Schmidt A. M., Yan S. D., Zou Y. S., Weidman E., Pinsky D., Nowygrod R., Neeper M., Przysiecki C., Shaw A. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. Am J Pathol. 1993 Dec;143(6):1699–1712. [PMC free article] [PubMed] [Google Scholar]
  6. Breviario F., Caveda L., Corada M., Martin-Padura I., Navarro P., Golay J., Introna M., Gulino D., Lampugnani M. G., Dejana E. Functional properties of human vascular endothelial cadherin (7B4/cadherin-5), an endothelium-specific cadherin. Arterioscler Thromb Vasc Biol. 1995 Aug;15(8):1229–1239. doi: 10.1161/01.atv.15.8.1229. [DOI] [PubMed] [Google Scholar]
  7. Brownlee M., Cerami A., Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988 May 19;318(20):1315–1321. doi: 10.1056/NEJM198805193182007. [DOI] [PubMed] [Google Scholar]
  8. Corada M., Mariotti M., Thurston G., Smith K., Kunkel R., Brockhaus M., Lampugnani M. G., Martin-Padura I., Stoppacciaro A., Ruco L. Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo. Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9815–9820. doi: 10.1073/pnas.96.17.9815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Davidson M. K., Russ P. K., Glick G. G., Hoffman L. H., Chang M. S., Haselton F. R. Reduced expression of the adherens junction protein cadherin-5 in a diabetic retina. Am J Ophthalmol. 2000 Feb;129(2):267–269. doi: 10.1016/s0002-9394(99)00323-2. [DOI] [PubMed] [Google Scholar]
  10. DeLisser H. M., Newman P. J., Albelda S. M. Molecular and functional aspects of PECAM-1/CD31. Immunol Today. 1994 Oct;15(10):490–495. doi: 10.1016/0167-5699(94)90195-3. [DOI] [PubMed] [Google Scholar]
  11. Dejana E., Corada M., Lampugnani M. G. Endothelial cell-to-cell junctions. FASEB J. 1995 Jul;9(10):910–918. [PubMed] [Google Scholar]
  12. Esposito C., Gerlach H., Brett J., Stern D., Vlassara H. Endothelial receptor-mediated binding of glucose-modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant properties. J Exp Med. 1989 Oct 1;170(4):1387–1407. doi: 10.1084/jem.170.4.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Esser S., Lampugnani M. G., Corada M., Dejana E., Risau W. Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells. J Cell Sci. 1998 Jul;111(Pt 13):1853–1865. doi: 10.1242/jcs.111.13.1853. [DOI] [PubMed] [Google Scholar]
  14. Garlanda C., Parravicini C., Sironi M., De Rossi M., Wainstok de Calmanovici R., Carozzi F., Bussolino F., Colotta F., Mantovani A., Vecchi A. Progressive growth in immunodeficient mice and host cell recruitment by mouse endothelial cells transformed by polyoma middle-sized T antigen: implications for the pathogenesis of opportunistic vascular tumors. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7291–7295. doi: 10.1073/pnas.91.15.7291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gotsch U., Borges E., Bosse R., Böggemeyer E., Simon M., Mossmann H., Vestweber D. VE-cadherin antibody accelerates neutrophil recruitment in vivo. J Cell Sci. 1997 Mar;110(Pt 5):583–588. doi: 10.1242/jcs.110.5.583. [DOI] [PubMed] [Google Scholar]
  16. Gulino D., Delachanal E., Concord E., Genoux Y., Morand B., Valiron M. O., Sulpice E., Scaife R., Alemany M., Vernet T. Alteration of endothelial cell monolayer integrity triggers resynthesis of vascular endothelium cadherin. J Biol Chem. 1998 Nov 6;273(45):29786–29793. doi: 10.1074/jbc.273.45.29786. [DOI] [PubMed] [Google Scholar]
  17. Khan B. V., Harrison D. G., Olbrych M. T., Alexander R. W., Medford R. M. Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9114–9119. doi: 10.1073/pnas.93.17.9114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kirstein M., Brett J., Radoff S., Ogawa S., Stern D., Vlassara H. Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging. Proc Natl Acad Sci U S A. 1990 Nov;87(22):9010–9014. doi: 10.1073/pnas.87.22.9010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lampugnani M. G., Corada M., Andriopoulou P., Esser S., Risau W., Dejana E. Cell confluence regulates tyrosine phosphorylation of adherens junction components in endothelial cells. J Cell Sci. 1997 Sep;110(Pt 17):2065–2077. doi: 10.1242/jcs.110.17.2065. [DOI] [PubMed] [Google Scholar]
  20. Lampugnani M. G., Corada M., Caveda L., Breviario F., Ayalon O., Geiger B., Dejana E. The molecular organization of endothelial cell to cell junctions: differential association of plakoglobin, beta-catenin, and alpha-catenin with vascular endothelial cadherin (VE-cadherin). J Cell Biol. 1995 Apr;129(1):203–217. doi: 10.1083/jcb.129.1.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lampugnani M. G., Dejana E. Interendothelial junctions: structure, signalling and functional roles. Curr Opin Cell Biol. 1997 Oct;9(5):674–682. doi: 10.1016/s0955-0674(97)80121-4. [DOI] [PubMed] [Google Scholar]
  22. Lampugnani M. G., Resnati M., Raiteri M., Pigott R., Pisacane A., Houen G., Ruco L. P., Dejana E. A novel endothelial-specific membrane protein is a marker of cell-cell contacts. J Cell Biol. 1992 Sep;118(6):1511–1522. doi: 10.1083/jcb.118.6.1511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Leach L., Eaton B. M., Westcott E. D., Firth J. A. Effect of histamine on endothelial permeability and structure and adhesion molecules of the paracellular junctions of perfused human placental microvessels. Microvasc Res. 1995 Nov;50(3):323–337. doi: 10.1006/mvre.1995.1062. [DOI] [PubMed] [Google Scholar]
  24. Lewalle J. M., Bajou K., Desreux J., Mareel M., Dejana E., Noël A., Foidart J. M. Alteration of interendothelial adherens junctions following tumor cell-endothelial cell interaction in vitro. Exp Cell Res. 1997 Dec 15;237(2):347–356. doi: 10.1006/excr.1997.3799. [DOI] [PubMed] [Google Scholar]
  25. Li Y. M., Steffes M., Donnelly T., Liu C., Fuh H., Basgen J., Bucala R., Vlassara H. Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor aminoguanidine. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3902–3907. doi: 10.1073/pnas.93.9.3902. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Matsumura T., Wolff K., Petzelbauer P. Endothelial cell tube formation depends on cadherin 5 and CD31 interactions with filamentous actin. J Immunol. 1997 Apr 1;158(7):3408–3416. [PubMed] [Google Scholar]
  27. Miyata T., Hori O., Zhang J., Yan S. D., Ferran L., Iida Y., Schmidt A. M. The receptor for advanced glycation end products (RAGE) is a central mediator of the interaction of AGE-beta2microglobulin with human mononuclear phagocytes via an oxidant-sensitive pathway. Implications for the pathogenesis of dialysis-related amyloidosis. J Clin Invest. 1996 Sep 1;98(5):1088–1094. doi: 10.1172/JCI118889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Navarro P., Ruco L., Dejana E. Differential localization of VE- and N-cadherins in human endothelial cells: VE-cadherin competes with N-cadherin for junctional localization. J Cell Biol. 1998 Mar 23;140(6):1475–1484. doi: 10.1083/jcb.140.6.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rabiet M. J., Plantier J. L., Rival Y., Genoux Y., Lampugnani M. G., Dejana E. Thrombin-induced increase in endothelial permeability is associated with changes in cell-to-cell junction organization. Arterioscler Thromb Vasc Biol. 1996 Mar;16(3):488–496. doi: 10.1161/01.atv.16.3.488. [DOI] [PubMed] [Google Scholar]
  30. Rojas A., Romay S., González D., Herrera B., Delgado R., Otero K. Regulation of endothelial nitric oxide synthase expression by albumin-derived advanced glycosylation end products. Circ Res. 2000 Feb 18;86(3):E50–E54. doi: 10.1161/01.res.86.3.e50. [DOI] [PubMed] [Google Scholar]
  31. Rumble J. R., Cooper M. E., Soulis T., Cox A., Wu L., Youssef S., Jasik M., Jerums G., Gilbert R. E. Vascular hypertrophy in experimental diabetes. Role of advanced glycation end products. J Clin Invest. 1997 Mar 1;99(5):1016–1027. doi: 10.1172/JCI119229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sandig M., Voura E. B., Kalnins V. I., Siu C. H. Role of cadherins in the transendothelial migration of melanoma cells in culture. Cell Motil Cytoskeleton. 1997;38(4):351–364. doi: 10.1002/(SICI)1097-0169(1997)38:4<351::AID-CM5>3.0.CO;2-6. [DOI] [PubMed] [Google Scholar]
  33. Schmidt A. M., Hori O., Cao R., Yan S. D., Brett J., Wautier J. L., Ogawa S., Kuwabara K., Matsumoto M., Stern D. RAGE: a novel cellular receptor for advanced glycation end products. Diabetes. 1996 Jul;45 (Suppl 3):S77–S80. doi: 10.2337/diab.45.3.s77. [DOI] [PubMed] [Google Scholar]
  34. Simionescu M., Simionescu N. Endothelial transport of macromolecules: transcytosis and endocytosis. A look from cell biology. Cell Biol Rev. 1991;25(1):5–78. [PubMed] [Google Scholar]
  35. Singh R., Barden A., Mori T., Beilin L. Advanced glycation end-products: a review. Diabetologia. 2001 Feb;44(2):129–146. doi: 10.1007/s001250051591. [DOI] [PubMed] [Google Scholar]
  36. Stitt A. W., He C., Friedman S., Scher L., Rossi P., Ong L., Founds H., Li Y. M., Bucala R., Vlassara H. Elevated AGE-modified ApoB in sera of euglycemic, normolipidemic patients with atherosclerosis: relationship to tissue AGEs. Mol Med. 1997 Sep;3(9):617–627. [PMC free article] [PubMed] [Google Scholar]
  37. Stitt A. W., He C., Vlassara H. Characterization of the advanced glycation end-product receptor complex in human vascular endothelial cells. Biochem Biophys Res Commun. 1999 Mar 24;256(3):549–556. doi: 10.1006/bbrc.1999.0291. [DOI] [PubMed] [Google Scholar]
  38. Suzuki S., Sano K., Tanihara H. Diversity of the cadherin family: evidence for eight new cadherins in nervous tissue. Cell Regul. 1991 Apr;2(4):261–270. doi: 10.1091/mbc.2.4.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Vlassara H., Bucala R., Striker L. Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging. Lab Invest. 1994 Feb;70(2):138–151. [PubMed] [Google Scholar]
  40. Wautier J. L., Zoukourian C., Chappey O., Wautier M. P., Guillausseau P. J., Cao R., Hori O., Stern D., Schmidt A. M. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Invest. 1996 Jan 1;97(1):238–243. doi: 10.1172/JCI118397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Yamagishi S. i., Yonekura H., Yamamoto Y., Katsuno K., Sato F., Mita I., Ooka H., Satozawa N., Kawakami T., Nomura M. Advanced glycation end products-driven angiogenesis in vitro. Induction of the growth and tube formation of human microvascular endothelial cells through autocrine vascular endothelial growth factor. J Biol Chem. 1997 Mar 28;272(13):8723–8730. doi: 10.1074/jbc.272.13.8723. [DOI] [PubMed] [Google Scholar]
  42. Yan S. D., Schmidt A. M., Anderson G. M., Zhang J., Brett J., Zou Y. S., Pinsky D., Stern D. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem. 1994 Apr 1;269(13):9889–9897. [PubMed] [Google Scholar]
  43. Zimmerman G. A., McIntyre T. M., Prescott S. M. Adhesion and signaling in vascular cell--cell interactions. J Clin Invest. 1996 Oct 15;98(8):1699–1702. doi: 10.1172/JCI118967. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES