Angiopoietin-1 Protects Against the Development of Cardiac Allograft Arteriosclerosis

Abstract

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.

Periadventitial angiopoietin-1 gene transfer induces angiogenesis in rabbit carotid arteries

“…Recently, Ang1 was also reported to protect vessels against the development of arteriosclerosis in cardiac allografts. 31 Edema and inflammation were also reported in the rabbit skeletal muscles after VEGF-A gene therapy. 32 In an earlier study by our group, delivery of the AdvVEGF-A into the periadventitial space of the carotid arteries resulted in a significant increase in inflammatory infiltrates 15 as compared to the controls.…”

Allograft Arteriosclerosis and Immune-Driven Angiogenesis

“…Their previous work 14 showed that vascular endothelial growth factor (VEGF) enhanced formation of these lesions. In their current article, 13 they show that its endogenous antagonist, angiopoietin-1, can forestall lesion formation. These observations draw attention to the role of microvessels in this disease.…”

“…Later studies showed that during the allogeneic response in vitro, T lymphocytes produce angiogenic growth factors including VEGF. 17,18 Thus, the observations of Nykänen et al 13 may have particular relevance to this special form of arteriosclerosis. In addition to angiopoietin, transplanted hearts can overexpress another endogenous modulator of angiogenesis.…”

“…15 Anti-angiogenic strategies can limit experimental atherogenesis, and the results of Nykänen et al 13 extend this concept to allograft vasculopathy. However, the story of the microvasculature in allografts is even more complex than in usual atherosclerosis.…”

“…In this issue of Circulation, Nykänen et al 13 show that angiopoietin-1 can protect against the development of arteriosclerosis in allografted rat hearts. Their previous work 14 showed that vascular endothelial growth factor (VEGF) enhanced formation of these lesions.…”