Abstract 286: Vein Graft Thrombosis and Neointimal Hyperplasia Can be Potentiated by Angiopoeitins-1 and -2
Endothelial survival and vascular integrity are promoted by angiopoietin-1 (Ang1), while vascular destabilization and remodeling are promoted by angiopoietin-2 (Ang2). These proteins are potential therapeutic targets for preventing endothelial damage, like that which triggers vein graft neointimal hyperplasia (NH). We therefore tested the hypothesis that vein graft NH would be mitigated by systemic administration of Ang1 and aggravated by Ang2. C57Bl/6 mice underwent carotid artery interposition vein grafting with the inferior vena cava of syngeneic donors. Vein graft donor and recipient mice were injected I.V. 3 days pre-operatively with recombinant adenoviruses (1×1010 pfu) encoding Ang1, Ang2, or no protein (vector virus); a parallel cohort received no virus (n ≥ 5 / group). Serial serum samples demonstrated Ang1 and -2 overexpression for ≥3 weeks after infection (by immunoblot), in Ang1- and Ang2-virus-treated mice. Vein grafts were harvested 4 weeks postoperatively after perfusion fixation, and cross sections from the middle of each graft were analyzed for morphometry. Vein grafts from vector virus-treated mice were all patent, and indistinguishable from those of mice treated with no virus: neointimal and medial areas were 160 ± 20 vs. 150 ± 20 μm2 (×103), and 140 ± 10 vs. 130 ± 10 μm2 (×103), respectively. In contrast, thrombosis occluded vein grafts from 67% of Ang1-treated (P < 0.05) and 17% of Ang2-treated mice, even though Ang concentrations equivalent to those in serum from these mice did not affect platelet aggregation in vitro. Furthermore, Ang2 treatment augmented vein graft neointimal area 2-fold compared with control grafts (300 ± 30 vs. 150 ± 20 μm2 (×103), P<0.05), but had no effect on medial area. In two patent grafts, Ang1 treatment did not affect neointimal or medial thickness. The extent of endothelialization (Tie2 immunostain) was reduced by 35% in vein grafts from Ang2-treated mice (P<0.05). We conclude that high plasma levels of Ang1 can lead to vein graft thrombosis, and that blockade of endogenous Ang1 activity by systemically overexpressed Ang2 exacerbates vein graft NH, in part by impairing endothelialization. These findings have important implications for the use of angiopoietins as potential treatment for vascular diseases.