title: T-cadherin is present on endothelial microparticles and is elevated in plasma in early atherosclerosis.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  Immunoblotting showed the presence 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 = 30), and increased levels in the plasma from patients with non-significant atherosclerosis (9.23 ± 2.61 ng/mL, n = 63) and patients with chronic coronary artery disease (6.93 ± 1.31 ng/mL, n = 162). In both patient groups there was a significant (P = 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 EC-derived 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital, ZLF 316 Hebelstrasse 20, CH 4031, Basel, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Philippova
authors.forename: Yves
authors.initials: Y
authors.lastname: Suter
authors.forename: Stefan
authors.initials: S
authors.lastname: Toggweiler
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Schoenenberger
authors.forename: Manjunath B
authors.initials: MB
authors.lastname: Joshi
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Kyriakakis
authors.forename: Paul
authors.initials: P
authors.lastname: Erne
authors.forename: Thérèse J
authors.initials: TJ
authors.lastname: Resink
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D015820:Cadherins / Q000378:metabolism*; D055252:Cell-Derived Microparticles / Q000378:metabolism; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000175:diagnosis*; D042241:Early Diagnosis; D004730:Endothelium, Vascular / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
chemical_list: D015820:Cadherins; C099972:H-cadherin