3-Deazaadenosine inhibits vasa vasorum neovascularization in aortas of ApoE^-/-/LDL^-/- double knockout mice

Background: Atherosclerosis and inflammation/angiogenesis are strongly associated including growth of vasa vasorum (VV) and plaque neovascularization, but a causative role for neovascularization has still not been established. Hence, we investigated the effect of 3-deazaadenosine (c³Ado), an anti-inflammatory and anti-proliferative drug, on plaque progression and VV neovascularization in apoE^-/-/LDL^-/- double knockout mice. Methods: The arterial trees from apoE^-/-/LDL^-/- mice with, or without c³Ado at the age of 16 weeks (n = 10), 18 weeks (n = 8) and 20 weeks (n = 7) were infused in situ with Microfil, and the aortas harvested and scanned with micro-CT (12 μm cubic voxel). We characterized plaque volume and VV luminal volume along the descending aorta using Analyze 6.0 software. Cellular effects of c³Ado on human endothelial and vascular smooth muscle cells were investigated in cell cultures and on nylon cDNA expression arrays. Results: Lesions spatially connected to VV increased from 16 to 20 weeks significantly (p < 0.001). The volume of atherosclerotic lesions was significantly reduced in animals treated with c³Ado (p < 0.01). This was accompanied by a significant decrease of vasa vasorum neovascularization along the descending aorta (p < 0.01). Using nylon cDNA expression arrays, we identified the regulation of anti-proliferative, anti-inflammatory genes in human smooth muscle cells which might be involved in the anti-angiogenic effects of c³Ado. Moreover, c³Ado dose-dependently prevented the proliferation and migration of human coronary artery endothelial cells in vitro. Conclusion: The smaller lesion volume in animals treated with c³Ado was closely associated with a reduced VV neovascularization, suggesting a direct relationship between lesion growth and VV development.