Vascular Smooth Muscle Cell Endovascular Therapy Stabilizes Already Developed Aneurysms in a Model of Aortic Injury Elicited by Inflammation and Proteolysis

Changing locally the biology of arterial aneurysms to promote healing and stability could represent an alternative to prosthetic treatments. Although previous studies using genetic or pharmacological tools have been successful at preventing the degeneration of a normal artery into an aneurysm,1–4 none of these studies addressed the question of whether already-formed experimental aneurysms could be stabilized by a nonprosthetic approach. Molecular and cellular mechanisms promoting already-formed aneurysm expansion are poorly understood. As a consequence, the structural and biologic changes required to stabilize already formed aneurysms are unknown. The degradation of arterial extracellular matrix by proteases has been shown to be instrumental in the formation of aneurysms, eg, the degeneration of a normal vessel into an aneurysm, regardless the initial mechanism triggering proteolysis, in atherosclerosis, inflammatory vascular diseases and in experimental models.4–8 Studies from human samples have shown that matrix metalloproteinases (MMPs), along with 2 other proteolytic enzyme families, are present in excess in aortic aneurysms.9,10 The role of MMPs in aneurysm formation has been validated by inhibition experiments, or gene expression invalidation, in different animal models.1–4 However, whether the interruption of extracellular matrix degradation would be sufficient to stop aortic dilatation once it has started is poorly documented. Once extracellular matrix has been injured by proteolysis and aneurysm has formed, the vessel wall is composed of a fragmented medial elastic network, with abundant neovessels in the adventitia and infiltrating macrophages, T and B lymphocytes.9,11,12 The lumen is often separated from blood flow by a luminal thrombus. This disorganized, dilated vessel tends to dilate further,13 with no spontaneous tendency to recover a normal structure. Current treatments are based on the strengthening of the aorta, or its replacement, by means of a prosthesis.14,15 One very specific feature of aneurysmal walls is the depletion in vascular smooth muscle cells (VSMCs) in the media layer.4,8,11,12,16–20 In addition, no VSMCs are present in the luminal thrombus, which is an environment hostile to cell development. Overall, most of the wall mass of aortic aneurysms is depleted in VSMCs. In other pathologic conditions, such as atherosclerotic stenoses, restenosis, and response to injury,21–24 VSMCs appear to be the main cellular component of arterial healing. We hypothesized that adding VSMCs could restore aneurysmal healing capabilities and function, eg, the ability to support hemodynamic constraint without expanding further. The aims of this study were to set-up a model of already-formed, and expanding, aortic aneurysm and to test the impact of VSMC seeding through an endoluminal catheter on expansion, MMP-dependent proteolytic balance regulation and wall structure.