Correlation of Vasa Vasorum Neovascularization and Plaque Progression in Aortas of Apolipoprotein E ^−/− /Low-Density Lipoprotein ^−/− Double Knockout Mice

Abstract

Objective-We hypothesized that apolipoprotein E (apoE)Ϫ/Ϫ /low-density lipoprotein (LDL) Ϫ/Ϫ double knockout mice might develop vasa vasorum (VV) in association with advanced lesion formation. Methods and Results-Aortas from apoEϪ/Ϫ /LDL Ϫ/Ϫ mice aged 16, 18, 20, or 80 weeks were infused in situ with Microfil, harvested, and scanned with micro-computed tomography (CT). We characterized plaque volume and CT "density" as well as VV luminal volume along the aorta using Analyze 6.0 software. Results were complemented by a detailed histological plaque classification according to American Heart Association guidelines. From 16 to 80 weeks, plaque volume and VV opacified lumen volume increased with age (PϽ0.001). The 3-dimensional micro-CT images of arterial and venous VV trees allowed perfusion territories to be delineated. The spatial location and magnitude of VV density and adventitial inflammation were strongly correlated in advanced atherosclerotic lesions (rϭ0.91) and identified as an independent correlate to advanced lesions. At age 80 weeks, VV luminal volume was increased 20-fold compared with animals at age 16 weeks (PϽ0.001). Micro-CT showed that adventitial VV communicate with intraplaque microvessels. Conclusion-Our

Development of a Magnetic Resonance Imaging Protocol for the Characterization of Atherosclerotic Plaque by Using Vascular Cell Adhesion Molecule-1 and Apoptosis-Targeted Ultrasmall Superparamagnetic Iron Oxide Derivatives

“…An acquisition time at 20 to 30 minutes after contrast agent administration could be optimal, because after this time a nonspecific plaque accumulation may occur, as suggested by the control contrast agent, USPIO-PEG. This could be driven by the enhanced permeability and retention (EPR) effect in areas with leaky vasculature (ie, hypervascularity, enhanced permeability, and low washout), 28 the same as in tumors. The contrast related to the EPR effect is illustrated by USPIO-PEG, which is responsible for 70% of the specific plaque enhancement at very late imaging times after administration (ie, 221 minutes); 32 minutes after administration, the plaque contrast produced by USPIO-PEG was as low as 20% of the maximum enhancement attained with USPIO-R832 and USPIO-R826.…”

Akt pathway is hypoactivated by synergistic actions of diabetes mellitus and hypercholesterolemia resulting in advanced coronary artery disease

“…Multiple studies have demonstrated the importance of VV neovascularization in the development of atherosclerosis (2,18,22,31,32,42,44), and VEGF-induced neovascularization has been postulated to be a therapeutic target to reduce atherosclerosis (21,43). An interesting finding from our experiments is that VEGF-induced neovascularization was present despite hypoactivation of Akt.…”

Angiogenesis Inhibitor, Endostar, Prevents Vasa Vasorum Neovascularization in a Swine Atherosclerosis Model

“…Previous studies have shown that vasa vasorum neovascularization increases in both early and advanced AS [5][6][7] . Vasa vasorum neovascularization is also strongly associated with inflammatory infiltration, lipid deposition, intraplaque hemorrhage, and hemosiderin deposit [8][9][10][11] .…”