Abstract 287: Oxidative Stress Modulates Vascular Smooth Muscle Cell Phenotype via Connective Tissue Growth Factor in Thoracic Aortic Aneurysm
Rationale. Thoracic Aortic Aneurysm (TAA) is characterized by a dysregulation of cellular and extracellular components of the aortic wall which contribute to the weakening of the ascending aorta. Oxidative stress has long been implicated in the pathogenesis of aneurysms for its role in inducing cellular apoptosis and matrix degradation. However, the link between oxidative stress and TAA formation remains to be firmly established. Connective Tissue Growth Factor (CTGF) regulates matrix biosynthesis as well as Vascular Smooth Muscle Cells (VSMC) proliferation and apoptosis. We hypothesized that Reactive Oxygen Species (ROS), modulated by altered hemodynamic conditions, could regulate VSMC phenotype and matrix composition via CTGF, affecting - in turn - the aortic tissue structure.
Methods. Finite element analysis (FEA) based on computed tomography geometries was used to estimate wall stress in control and TAA patients. In vitro and ex vivo studies on human tissues and isolated VSMC were used to demonstrate the correlation between ROS, CTGF, and VSMC synthetic phenotype in TAA development. Results were validated in vivo by a murine model of TAA based on Angiotensin II (AngII) infusion.
Results. TAA patients have higher wall stress in the ascending aorta than non-dilated patients. High aortic wall stress is associated with increased levels of ROS, media degeneration and accumulation of synthetic VSMCs in TAA tissues. ROS directly induce CTGF expression, which modulates synthetic VSMC phenotype in human isolated cells. ROS effect is reverted in vitro either using a neutralizing antibody against CTGF or by antioxidant administration. In AngII- induced TAA in mice, medial thickening and luminal expansion of the proximal aorta are associated with ROS accumulation, CTGF up-regulation and VSMC with a synthetic phenotype as seen in human specimens.
Conclusions. Increased peak wall stress correlates with change in VSMCs towards a synthetic phenotype mediated by ROS accumulation via CTGF. Understanding the molecular mechanisms that regulate VSMCs towards a synthetic phenotype could unveil new regulatory pathways for aortic homeostasis and identify new therapeutic targets for patients at risk of aortic dissection and rupture.
- © 2013 by American Heart Association, Inc.