Abstract 85: Atherosclerosis Induces Thoracic and Abdominal Aortic Disease in Preaneurysmal Transgenic Fibulin-4 Mice
Extracellular matrix degradation in the aortic wall plays an important role in the formation and progression of aneurysms. In mice, a deficiency of the extracellular matrix protein fibulin-4, induces matrix metalloproteinases (MMP) upregulation and transforming growth factor-β dysregulation. This results in the formation of aneurysms in the thoracic aorta of homozygous Fibulin-4R/R mice. In humans, aneurysms usually develop in the abdominal aorta during aging and are most often associated with atherosclerosis. To investigate the molecular mechanisms underlying the interaction of aneurysmatic and atherosclerotic aortic disease we developed a new mouse model.
Fibulin-4 knockdown (Fibulin-4+/R) mice, which display mild extracellular matrix changes, were crossbred with atherosclerotic ApoE-/- mice. The double mutant mice were fed a high fat diet for 10 or 20 weeks starting at 9 weeks after birth. Thoracic and abdominal aortic architecture were assessed in vivo using high-resolution ultrasound. MMP activity in the aorta was determined using fluorescent imaging with protease-activatable near-infrared fluorescence probes. Following sacrifice, plaque burden was evaluated through quantitative oil-red-o staining and histological analysis.
Already after 10 weeks of high fat diet, ApoE-/-Fibulin-4+/R mice displayed increased matrix metalloproteinase activity in the abdominal aorta and increased plaque formation at the level of the visceral arteries as compared with ApoE-/-Fibulin-4+/+ mice, with further increases observed after 20 weeks of high fat diet. Surprisingly, after 20 weeks high fat diet the aortic diameter increased up to 60% in the aortic arch and 20% in the abdominal aorta in the ApoE-/-Fibulin-4+/R mice as compared with ApoE-/-Fibulin-4+/= mice.
This novel mutant mouse model is the first viable murine model which mimics the clinical situation of coexistent aneurysm formation and atherogenesis. It provides the opportunity to unravel the biological processes underlying aortic wall degeneration and to identify markers that elucidate key events in the early stages of the pathogenic sequence that culminates in an aneurysm. We identified that partial degradation of the extracellular matrix under the influence of atherosclerosis leads to aortic dilatation. In addition, we show that protease-activatable fluorescent sensors are promising new tools to monitor non-invasively the enhanced matrix metalloproteinases activity in the aortic wall that precedes aortic wall degeneration.
- © 2012 by American Heart Association, Inc.