title: Ischemia-Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts.
abstract: Organ damage and innate immunity during heart transplantation may evoke adaptive immunity with serious consequences. Because lymphatic vessels bridge innate and adaptive immunity, they are critical in immune surveillance; however, their role in ischemia-reperfusion injury (IRI) in allotransplantation remains unknown. We investigated whether the lymphangiogenic VEGF-C/VEGFR3 pathway during cardiac allograft IRI regulates organ damage and subsequent interplay between innate and adaptive immunity. We found that cardiac allograft IRI, within hours, increased graft VEGF-C expression and lymphatic vessel activation in the form of increased lymphatic VEGFR3 and adhesion protein expression. Pharmacological VEGF-C/VEGFR3 stimulation resulted in early lymphatic activation and later increase in allograft inflammation. In contrast, pharmacological VEGF-C/VEGFR3 inhibition during cardiac allograft IRI decreased early lymphatic vessel activation with subsequent dampening of acute and chronic rejection. Genetic deletion of VEGFR3 specifically in the lymphatics of the transplanted heart recapitulated the survival effect achieved by pharmacological VEGF-C/VEGFR3 inhibition. Our results suggest that tissue damage rapidly changes lymphatic vessel phenotype, which, in turn, may shape the interplay of innate and adaptive immunity. Importantly, VEGF-C/VEGFR3 inhibition during solid organ transplant IRI could be used as lymphatic-targeted immunomodulatory therapy to prevent acute and chronic rejection.
authors.affiliation: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.|Cardiac Surgery, University Hospital Munich, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Dashkevich
authors.affiliation: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Raissadati
authors.affiliation: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: S O
authors.initials: SO
authors.lastname: Syrjälä
authors.affiliation: Wihuri Research Institute, Translational Cancer Biology Program and Helsinki University Central Hospital, Research Programs Unit, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: G
authors.initials: G
authors.lastname: Zarkada
authors.affiliation: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: M A I
authors.initials: MA
authors.lastname: Keränen
authors.affiliation: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: R
authors.initials: R
authors.lastname: Tuuminen
authors.affiliation: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: R
authors.initials: R
authors.lastname: Krebs
authors.affiliation: Wihuri Research Institute, Translational Cancer Biology Program and Helsinki University Central Hospital, Research Programs Unit, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Anisimov
authors.affiliation: Wihuri Research Institute, Translational Cancer Biology Program and Helsinki University Central Hospital, Research Programs Unit, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Jeltsch
authors.affiliation: Wihuri Research Institute, Translational Cancer Biology Program and Helsinki University Central Hospital, Research Programs Unit, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: V-M
authors.initials: VM
authors.lastname: Leppänen
authors.affiliation: Wihuri Research Institute, Translational Cancer Biology Program and Helsinki University Central Hospital, Research Programs Unit, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Alitalo
authors.affiliation: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.|Cardiac Surgery, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: A I
authors.initials: AI
authors.lastname: Nykänen
authors.affiliation: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.|Cardiac Surgery, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: K B
authors.initials: KB
authors.lastname: Lemström
mesh_terms: D064591:Allografts; D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006084:Graft Rejection / Q000378:metabolism* / Q000473:pathology; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D042583:Lymphangiogenesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D014019:Tissue Donors; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: antigen presentation; basic (laboratory) research; cardiology; immunobiology; heart transplantation; ischemia reperfusion injury (IRI); lymphocyte biology; organ transplantation; recognition; rejection; science; trafficking; translational research; vascular biology