Abstract 3599: ApolipoproteinA-I, the Major Protein Component of High Density Lipoproteins, Inhibits Tubulogenesis In Vitro and Neovascularisation in Response to Vascular Injury In Vivo
High density lipoproteins (HDL) are atheroprotective, thought principally due to reverse cholesterol transport and/or anti-inflammatory effects. Angiogenesis is implicated in atheroinflammation. We investigated the effects of apolipoproteinA-I (apoA-I), the major protein component of HDL, on angiogenesis in vitro and in an arterial injury model of neovascularization in vivo. To exclude confounding effects of other lipids, purified delipidated (lipid-free) apoA-I was used. We evaluated effects of apoA-I over a physiologic range (2– 8 μM) on key angiogenic processes in vitro, namely EC proliferation, migration (scratch wounding assay) and EC-specific tubulogenesis (EC & fibroblast co-culture model). Adventitial neovascularization was induced in mice by insertion of a non-occlusive collar around the femoral artery. The animals (5/group) received IV saline or apoA-I (8mg/kg), either at the time of, or 1 or 2 wk post-collar insertion. Mice were sacrificed 3wks post-insertion. Peri-arterial neovascularization and macrophage numbers were assessed by immunohistochemistry (IHC). ApoA-I significantly inhibited tubule formation, as assessed by IHC at 72h, in a dose-dependent fashion, without altering EC proliferation or migration (8μM apoA-I, tubule formation reduced by 33±7% v control, p<0.005). Peri-arterial collars induced a strong inflammatory adventitial neovascular response (9-fold increase Von Willebrand factor (vWF) immunostaining, 13-fold increase capillary no. v non-collared arteries). ApoA-I infusions administered at time of collar, 1 & 2 wk post-collar, dramatically reduced %adventitial vWF staining by 54±8, 51±7 and 58±7 v control respectively, as well as capillary no. by 47±11%, 40±7% and 50±11% respectively, v control (p<0.01 for all). Macrophages were significantly reduced in apoA-I infused mice at each time point (43±13%, 44±4% and 41±4% respectively), v control (p<0.01 for all). ApoA-I, the major protein of HDL, significantly inhibits both tubulogenesis in vitro and inflammatory neovascularization in an arterial injury model in vivo. HDL may have a role in modulating angiogenic processes, with potential relevance to atherosclerotic plaque neovascularization.