T-cadherin is present on endothelial microparticles and is elevated in plasma in early atherosclerosis

Maria Philippova, Yves Suter, Stefan Toggweiler, Andreas W. Schoenenberger, Manjunath B. Joshi, Emmanouil Kyriakakis, Paul Erne, Thérèse J. Resink
2010 European Heart Journal  
Aims The presence of endothelial cell (EC)-derived surface molecules in the circulation is among hallmarks of endothelial activation and damage in vivo. Previous investigations suggest that upregulation of T-cadherin (T-cad) on the surface of ECs may be a characteristic marker of EC activation and stress. We investigated whether T-cad might also be shed from ECs and in amounts reflecting the extent of activation or damage. Methods and results Immunoblotting showed the presence of T-cad protein
more » ... e of T-cad protein in the culture medium from normal proliferating ECs and higher levels in the medium from stressed/apoptotic ECs. Release of T-cad into the circulation occurs in vivo and in association with endothelial dysfunction. Sandwich ELISA revealed negligible T-cad protein in the plasma of healthy volunteers (0.90 + 0.90 ng/mL, n ¼ 30), and increased levels in the plasma from patients with non-significant atherosclerosis (9.23 + 2.61 ng/mL, n ¼ 63) and patients with chronic coronary artery disease (6.93 + 1.31 ng/mL, n ¼ 162). In both patient groups there was a significant (P ¼ 0.043) dependency of T-cad and degree of endothelial dysfunction as measured by reactive hyperaemia peripheral tonometry. Flow cytometry analysis showed that the major fraction of T-cad was released into the EC culture medium and the plasma as a surface component of ECderived annexin V-and CD144/CD31-positive microparticles (MPs). Gain-of-function and loss-of-function studies demonstrate that MP-bound T-cad induced Akt phosphorylation and activated angiogenic behaviour in target ECs via homophilic-based interactions. Conclusion Our findings reveal a novel mechanism of T-cad-dependent signalling in the vascular endothelium. We identify T-cad as an endothelial MP antigen in vivo and demonstrate that its level in plasma is increased in early atherosclerosis and correlates with endothelial dysfunction. ---
doi:10.1093/eurheartj/ehq206 pmid:20584775 fatcat:mipvo75ipbf3lm25jtfeutyneu