Anti-HLA I antibodies induce VEGF production by endothelial cells,which increases proliferation and paracellular permeability |
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| Authors: | Michael Bieri Melinda Oroszlan Anikò Farkas Nathalie Ligeti Jürg Bieri Paul Mohacsi |
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| Institution: | 1. Department of Pharmacology & Toxicology, Georgia Health Sciences University, Augusta, GA, USA;2. Department of Physiology, Georgia Health Sciences University, Augusta, GA, USA;3. Department of Cell Biology and Anatomy, Georgia Health Sciences University, Augusta, GA, USA;4. Vascular Biology Center, Georgia Health Sciences University, Augusta, GA, USA;5. Department of Cardiology, University of Chicago Medicine, Chicago, IL, USA;1. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan;2. Department of Neurology, School of Medicine, National Yang-Ming University, Taipei, Taiwan;3. Division of Cardiology, Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan;4. Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan;5. Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan;6. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan;7. Department of Occupational Medicine, Kaohsiung Municipal Hsiaokang Hospital, Kaohsiung, Taiwan;8. Section of Cardiology, Department of Medicine, University of Chicago, Chicago, USA;9. Department of Genome Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;10. Department of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan |
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| 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. |
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