Perioperative single-dose VEGF-C/D inhibitor enhances cardiac allograft survival and prevents chronic rejection by regulating lymphatic endothelial cell activation

• Published in: The Thoracic and Cardiovascular Surgeon
• Main Authors: Dashkevich, A., Syrjälä, S.O., Keränen, M.A., Krebs, R., Nykänen, A.I., Alitalo, K., Lemström, K.B.
• Format: Conference Proceeding
• Language: English
• Published: 10.02.2014
• ISSN: 0171-6425; 1439-1902
• DOI: 10.1055/s-0034-1367258

Objectives: VEGF-C/D/VEGFR-3 signaling may regulate lymphatic vessel activation and the initiation of alloimmunity after transplantation. We investigated the effect of perioperative intracoronary injection of synthetic VEGF-C/D inhibitor on lymphatic vessel activation, antigen-presenting cell trafficking and subsequent development of alloimmune responses in rat cardiac allografts. Methods: We perfused the coronaries of DA donor rat hearts ex vivo with VEGF-C/D inhibitor or PBS and preserved the grafts in +4°C PBS for 4 h and then transplanted the grafts to fully MHC-mismatched WF recipient rats. We analyzed ischemia-reperfusion injury, and acute and chronic rejection responses. In acute and chronic rejection models, the recipients received Cyclosporine A as immunosuppression. Results: At 6 h after the reperfusion, VEGF-C/D inhibitor did not affect the myocardial injury but reduced the number of LYVE-1+ lymphatic vessels expressing VEGFR-3, ICAM-1 and VCAM-1 in the allograft and reduced the number of dendritic cells migrating out of the allograft. VEGF-C/D inhibition enhanced allograft survival in acute rejection model. In chronic rejection model, VEGF-C/D inhibitor reduced allograft inflammation and prevented the development of cardiac fibrosis and vasculopathy. Conclusions: Intracoronary treatment with VEGF-C/D inhibitor prevented early activation of lymphatic endothelial cells and trapped dendritic cells into the allograft. This interfered with allorecognition resulting in reduced acute and chronic rejection responses. Our results suggest donor single-dose intracoronary treatment with VEGF-C/D inhibitor as a novel clinically feasible lymphatic vessel targeted immunomodulatory approach. Fig. 1: VEGF-C/D inhibitor prevented lymphatic vessel activation (seen as reduced expression of VEGFR-3 ( A ), ICAM-1 ( B ) and VCAM-1 ( C ) in LYVE-1+ lymphatics) and trapped dendritic cells in the allograft ( D ) at 6h after reperfusion. VEGF-C/D inhibitor improved cardiac allograft survival ( H ). VEGF-C/D inhibitor reduced cardiac fibrotic area ( E ) and arterial occlusion in the allograft ( F ), the incidence of arterial occlusion ( G ) and the influx of ED-1+ ( I ), CD4+ ( J ), CD-8+ ( K ) and MPO+ ( L ) inflammatory cells at 8 weeks after reperfusion. *p < 0.05, **p < 0.01, ***p < 0.001.