Angiopoietin-1 protects against the development of cardiac allograft arteriosclerosis.
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.


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.
Nykänen
Antti I
AI
Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Finland.
Krebs
Rainer
R
Saaristo
Anne
A
Turunen
Päivi
P
Alitalo
Kari
K
Ylä-Herttuala
Seppo
S
Koskinen
Petri K
PK
Lemström
Karl B
KB
D000256:Adenoviridae / Q000235:genetics; D043925:Angiogenesis Inducing Agents / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D002196:Capillaries / Q000737:chemistry; D002465:Cell Movement; D003324:Coronary Artery Disease / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D005822:Genetic Vectors; D006084:Graft Rejection / Q000378:metabolism; D016027:Heart Transplantation / Q000009:adverse effects*; D006412:Hematopoietic Stem Cells / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D007962:Leukocytes / Q000276:immunology; D008208:Lymphatic System / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D009363:Neoplasm Proteins / Q000032:analysis; D011518:Proto-Oncogene Proteins; D051381:Rats; D042787:Receptor, TIE-2
C467630:ANGPT1 protein, human; D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467629:Angpt1 protein, rat; D018952:Antigens, CD34; C105373:MEN1 protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D042787:Receptor, TIE-2