Oxidative stress modulates vascular smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm
| Autor: | Eric K. Shang, Giovanni Ferrari, Rachana Sainger, Robert C. Gorman, Benjamin M. Jackson, Joseph H. Gorman, Joseph E. Bavaria, Emanuela Branchetti, Paolo Poggio, Michael S. Parmacek, Eric K. Lai, Juan B. Grau |
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| Rok vydání: | 2013 |
| Předmět: |
Serum Response Factor
Pathology medicine.medical_specialty Vascular smooth muscle Physiology Finite Element Analysis Myocytes Smooth Muscle Biology medicine.disease_cause Thoracic aortic aneurysm Muscle Smooth Vascular Mice Physiology (medical) medicine.artery Ascending aorta medicine Animals Humans Vimentin ets-Domain Protein Elk-1 Aorta Aortic Aneurysm Thoracic Angiotensin II Connective Tissue Growth Factor Original Articles Anatomy medicine.disease Mice Inbred C57BL CTGF Oxidative Stress Phenotype cardiovascular system Reactive Oxygen Species Cardiology and Cardiovascular Medicine Oxidative stress Homeostasis |
| Zdroj: | Cardiovascular Research. 100:316-324 |
| ISSN: | 0008-6363 |
| DOI: | 10.1093/cvr/cvt205 |
| Popis: | Dissection and rupture of the ascending aorta are life-threatening conditions resulting in 80% mortality. Ascending aortic replacement in patients presenting with thoracic aortic aneurysm (TAA) is determined by metric measurement. However, a significant number of dissections occur outside of the parameters suggested by the current guidelines. We investigate the correlation among altered haemodynamic condition, oxidative stress, and vascular smooth muscle cell (VSMC) phenotype in controlling tissue homoeostasis. Methods and results We demonstrate using finite element analysis (FEA) based on computed tomography geometries that TAA patients have higher wall stress in the ascending aorta than non-dilated patients. We also show that altered haemodynamic conditions are associated with increased levels of reactive oxygen species (ROS), direct regulators of the VSMC phenotype in the microregional area of the ascending aorta. Usinginvitro andexvivo studies on human tissues, we show that ROS accumu- lation correlates with media layer degeneration and increased connective tissue growth factor (CTGF) expression, which modulate the synthetic VSMC phenotype. Results were validated by a murine model of TAA (C57BL/6J) based on Angio- tensin II infusion showing that medial thickening and luminal expansion of the proximal aorta is associated with the VSMC synthetic phenotype as seen in human specimens. Conclusions Increased peak wall stress correlates with change in VSMC towards a synthetic phenotype mediated by ROS accumula- tion via CTGF. Understanding the molecular mechanisms that regulate VSMC towards a synthetic phenotype could unveil new regulatory pathways of aortic homoeostasis and impact the risk-stratification tool for patients at risk of aortic dis- section and rupture. |
| Databáze: | OpenAIRE |
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