title: Anti-HLA I antibodies induce VEGF production by endothelial cells, which increases proliferation and paracellular permeability.
abstract: Anti-human leukocyte antigen class I (HLA I) antibodies were shown to activate several protein kinases in endothelial cells (ECs), which induces proliferation and cell survival. An important phenomenon in antibody-mediated rejection is the occurrence of interstitial edema. We investigated the effect of anti-HLA I antibodies on endothelial proliferation and permeability, as one possible underlying mechanism of edema formation. HLA I antibodies increased the permeability of cultured ECs isolated from umbilical veins. Anti-HLA I antibodies induced the production of vascular endothelial growth factor (VEGF) by ECs, which activated VEGF receptor 2 (VEGFR2) in an autocrine manner. Activated VEGFR2 led to a c-Src-dependent phosphorylation of vascular endothelial (VE)-cadherin and its degradation. Aberrant VE-cadherin expression resulted in impaired adherens junctions, which might lead to increased endothelial permeability. This effect was only observed after cross-linking of HLA I molecules by intact antibodies. Furthermore, our results suggest that increased endothelial proliferation following anti-HLA I treatment occurs via autocrine VEGFR2 activation. Our data indicate the ability of anti-HLA I to induce VEGF production in ECs. Transactivation of VEGFR2 leads to increased EC proliferation and paracellular permeability. The autocrine effect of VEGF on endothelial permeability might be an explanation for the formation of interstitial edema after transplantation.
authors: Laboratory of Heart Transplantation Immunology, Swiss Cardiovascular Center, Inselspital, University of Bern, 3010 Bern, Switzerland.
authors: Michael
authors: M
authors: Bieri
authors: Melinda
authors: M
authors: Oroszlan
authors: Anikò
authors: A
authors: Farkas
authors: Nathalie
authors: N
authors: Ligeti
authors: Jürg
authors: J
authors: Bieri
authors: Paul
authors: P
authors: Mohacsi
mesh_terms: D000906:Antibodies / Q000494:pharmacology*; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004487:Edema / Q000276:immunology; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007114:Immunization; D010766:Phosphorylation; D015398:Signal Transduction; D019108:Tight Junctions / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000906:Antibodies; D015820:Cadherins; D015395:Histocompatibility Antigens Class I; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2