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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:819.)
© 2007 American Heart Association, Inc.

Vascular Biology

VEGFR-1 and -2 Regulate Inflammation, Myocardial Angiogenesis, and Arteriosclerosis in Chronically Rejecting Cardiac Allografts

Olivier Raisky; Antti I. Nykänen; Rainer Krebs; Maria Hollmén; Mikko A.I. Keränen; Jussi M. Tikkanen; Roope Sihvola; Leena Alhonen; Petri Salven; Yan Wu; Daniel J. Hicklin; Kari Alitalo; Petri K. Koskinen; Karl B. Lemström

From the Cardiopulmonary Research Group, Transplantation Laboratory (A.I.N., R.K., M.H., M.A.I.K., J.M.T., R.S., P.K.K, K.B.L.), University of Helsinki and Helsinki University Central Hospital; Department of Medicine, Division of Nephrology (P.K.K.), Department of Cardiothoracic Surgery (K.B.L.), Helsinki University Central Hospital; Molecular Cancer Biology Laboratory (K.A.) and Institute of Biomedicine (P.S.), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences (L.A.), University of Kuopio, Finland; Hôpital Cardiologique Louis Pradel (O.R), Lyon, France; ImClone Systems Incorporated (Y.W., D.J.H.), New York.

Correspondence to Antti Nykänen, MD, Transplantation Laboratory, Haartman Institute, P.O.Box 21 (Haartmaninkatu 3), FIN-00014 University of Helsinki, Finland. E-mail Antti.Nykanen{at}Helsinki.Fi

Objective— Interplay between inflammation and angiogenesis is important in pathological reparative processes such as arteriosclerosis. We investigated how the two vascular endothelial growth factor receptors VEGFR-1 and -2 regulate these events in chronically rejecting cardiac allografts.

Methods and Results— Chronic rejection in mouse cardiac allografts induced primitive myocardial, adventitial, and intimal angiogenesis with endothelial expression of CD31, stem cell marker c-kit, and VEGFR-2. Experiments using marker gene mice or rats as cardiac allograft recipients revealed that replacement of cardiac allograft endothelial cells with recipient bone marrow– or non–bone marrow–derived cells was rare and restricted only to sites with severe injury. Targeting VEGFR-1 with neutralizing antibodies in mice reduced allograft CD11b⁺ myelomonocyte infiltration and allograft arteriosclerosis. VEGFR-2 inhibition prevented myocardial c-kit⁺ and CD31⁺ angiogenesis in the allograft, and decreased allograft inflammation and arteriosclerosis.

Conclusions— These results suggest interplay of inflammation, primitive donor-derived myocardial angiogenesis, and arteriosclerosis in transplanted hearts, and that targeting VEGFR-1 and -2 differentially regulate these pathological reparative processes.

Interplay between inflammation and angiogenesis is important in pathological reparative processes such as arteriosclerosis. We investigated how the two vascular endothelial growth factor receptors VEGFR-1 and -2 regulate these events in chronically rejecting cardiac allografts. Our results suggest interplay of inflammation, primitive donor-derived myocardial angiogenesis, and arteriosclerosis in transplanted hearts, and that targeting VEGFR-1 and -2 differentially regulate these pathological reparative processes.

Key Words: angiogenesis • inflammation • transplantation • arteriosclerosis • stem cells