Published Online
on February 17, 2003

A more recent version of this article appeared on March 11, 2003

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Submitted on August 28, 2002
Revised on November 25, 2002
Accepted on December 5, 2002

Angiopoietin-1 Protects Against the Development of Cardiac Allograft Arteriosclerosis

Antti I. Nykänen MD, Rainer Krebs MSc, Anne Saaristo MD, Päivi Turunen MSc, Kari Alitalo MD, PhD, Seppo Ylä-Herttuala MD, PhD, Petri K. Koskinen MD, PhD, and Karl B. Lemström MD, PhD^*

From the Cardiopulmonary Research Group, Transplantation Laboratory (A.I.N., R.K., P.K.K., K.B.L.), University of Helsinki and Helsinki University Central Hospital; Department of Medicine, Division of Nephrology (P.K.K.), and Department of Cardiothoracic Surgery (K.B.L.), Helsinki University Central Hospital; Molecular Cancer Biology Laboratory (K.A., A.S.), Biomedicum Helsinki, University of Helsinki, Helsinki, and A.I. Virtanen Institute for Molecular Sciences (S.Y.-H., P.T.), University of Kuopio, Kuopio, Finland.

^* To whom correspondence should be addressed. E-mail: karl.lemstrom{at}helsinki.fi.

Background--Angiopoietin (Ang)-1 is an angiogenic growth factor that counteracts the permeability and proinflammatory effects of vascular endothelial growth factor and other proinflammatory cytokines. Recently, we demonstrated that vascular endothelial growth factor enhances cardiac allograft arteriosclerosis. Here, we studied the roles of Ang1, its natural antagonist Ang2, and their receptor Tie2 in rat cardiac allograft arteriosclerosis.

Methods and Results--Heterotopic cardiac allografts and syngrafts were transplanted from Dark Agouti (DA) to Wistar-Furth rats and from DA to DA rats, respectively. Immunohistochemistry disclosed that only a few mesenchymal cells expressed Ang1 in normal hearts and syngrafts, whereas no immunoreactivity was found in cardiac allografts undergoing chronic rejection. Ang2 and Tie2 immunoreactivity was induced mainly in capillaries and postcapillary venules in chronic allografts when compared with syngeneic controls, but no immunoreactivity was found in arterial endothelium. Intracoronary perfusion of cardiac allografts with a clinical-grade adenoviral vector encoding human Ang1 (Ad.Ang1) protected against the development of allograft arteriosclerosis. Ad.Ang1 perfusion reduced Ang2 expression in microcirculation, the numbers of graft-infiltrating leukocytes, and the level of immunoactivation and interstitial fibrosis, as well as both the incidence and intensity of intimal lesions. Ad.Ang1 perfusion also increased CD34⁺ stem cell counts in peripheral blood.

Conclusions--Our findings suggest that the antiinflammatory properties of Ang1 may offer an entirely new therapeutic approach to prevent cardiac allograft arteriosclerosis.

Key words: angiogenesis • endothelium • inflammation • arteriosclerosis • transplantation

Related Article:

Allograft Arteriosclerosis and Immune-Driven Angiogenesis

Peter Libby and David Xiao-Ming Zhao
Circulation 2003 107: 1237-1239. [Extract] [Full Text]

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