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Background-Ischemia/reperfusion injury may have deleterious short-and long-term consequences for cardiac allografts.The underlying mechanisms involve microvascular dysfunction that may culminate in primary graft failure or untreatable chronic rejection. Methods and Results-Here, we report that rat cardiac allograft ischemia/reperfusion injury resulted in profound microvascular dysfunction that was prevented by donor treatment with peroral single-dose simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase and Rho GTPase inhibitor, 2 hours before graft procurement. During allograft preservation, donor simvastatin treatment inhibited microvascular endothelial cell and pericyte RhoA/Rho-associated protein kinase activation and endothelial cell-endothelial cell gap formation; decreased intragraft mRNA levels of hypoxia-inducible factor-1␣, inducible nitric oxide synthase, and endothelin-1; and increased heme oxygenase-1. Donor, but not recipient, simvastatin treatment prevented ischemia/reperfusion injury-induced vascular leakage, leukocyte infiltration, the no-reflow phenomenon, and myocardial injury. The beneficial effects of simvastatin on vascular stability and the no-reflow phenomenon were abolished by concomitant nitric oxide synthase inhibition with N-nitro-L-arginine methyl ester and RhoA activation by geranylgeranyl pyrophosphate supplementation, respectively. In the chronic rejection model, donor simvastatin treatment inhibited cardiac allograft inflammation, transforming growth factor-␤1 signaling, and myocardial fibrosis. In vitro, simvastatin inhibited transforming growth factor-␤1-induced microvascular endothelial-to-mesenchymal transition. Conclusions-Our results demonstrate that donor simvastatin treatment prevents microvascular endothelial cell and pericyte dysfunction, ischemia/reperfusion injury, and chronic rejection and suggest a novel, clinically feasible strategy to protect cardiac allografts. (Circulation. 2011;124:1138-1150.)Key Words: endothelium Ⅲ inflammation Ⅲ ischemia Ⅲ microcirculation Ⅲ transplantation R estoration of compromised blood flow is vital in vascular occlusion, but paradoxically, tissue reperfusion is often accompanied by significant morbidity and mortality. This is especially evident in heart transplantation in which ischemia/ reperfusion injury (IRI) may result in primary graft failure and the development of untreatable chronic rejection. [1][2][3] Clinically feasible organ preservation strategies are needed to limit early IRI, to blunt subsequent pathological immunological and tissue remodeling responses, and to prolong cardiac allograft recipient survival. Clinical Perspective on p 1150Endothelial cell (EC) dysfunction is a hallmark of IRI 4 -6 and the development of cardiac allograft fibrosis and arteriosclerosis, manifestations of chronic rejection. 2,3,7 IRI 5 and several IRIrelated factors such as hypoxia, thrombin, vascular endothelial growth factor, and RhoA GTPase activation are involved in EC-EC gap formation and compromised endothelial stability. 6,8 -10...

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.

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