Abstract Body (Do not enter title and authors here):
Objective:
The adventitial layer of the aorta contains the network of microvessels known as vasa vasorum. Previous work by our team revealed deficient vasa vasorum associated with medial hypoxia and upregulated adventitial thrombospondin-1 (TSP-1), an anti-angiogenic molecule, in human aortic aneurysm. We hypothesize that heightened TSP-1 in the ascending thoracic aorta induces aneurysmal degeneration through its anti-angiogenic effects on the vasa vasorum. We tested this hypothesis in a rabbit model via peri-adventitial delivery of ABT-510, a thrombospondin peptide mimetic.

Methods:
The ascending aorta was exposed in New Zealand White rabbits (n=16) and treated with ABT-510 proximally and a vehicle control distally. Echocardiography was undertaken immediately prior to the procedure and 14 days post-operatively. Adventitial vasa vasorum were quantified from H&E-stained sections. Elastin and collagen organization were assessed with Verhoeff-Van Gieson (VVG) and pentachrome staining as well as multiphoton microscopy. Immunodetection of Hypoxyprobe™ and alpha smooth muscle actin (αSMA) were also undertaken to identify hypoxia and smooth muscle cell content, respectively.

Results:
Echocardiography revealed an increase in aortic diameter over 14 days with ABT-510 treatment compared with control (42.27% ± 5.54 vs 20.99% ± 4.10, p=0.004). Histological analysis showed decreased vasa vasorum count (44.7 ± 9.19 vs 85.8 ± 12.89, p=0.048) and decreased vasa vasorum indexed cumulative area (0.013 ± 0.0037 vs 0.021 ± 0.0050 µm²/ µm² adventitial area, p=0.019). Immunodetection of Hypoxyprobe™ showed evidence of increased hypoxia. VVG, pentachrome, and immunodetection of αSMA showed decreased elastin content, increased deposition of ground substance, and areas of smooth muscle cell loss. Multiphoton microscopy demonstrated fragmented elastin fiber microarchitecture and decreased collagen content (Fig 1).

Conclusions:
Our study findings demonstrate a novel, clinically relevant model for thoracic aortic aneurysm through vasa vasorum inhibition that recapitulates features of cystic medial degeneration. This translational model could enable development of targeted, pro-regenerative therapies that restore perfusion to the aortic wall.