Oxidative stress modulates vascular smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm

Emanuela Branchetti, Paolo Poggio, Rachana Sainger, Eric Shang, Juan B. Grau, Benjamin M. Jackson, Eric K. Lai, Michael S. Parmacek, Robert C. Gorman, Joseph H. Gorman, Joseph E. Bavaria, Giovanni Ferrari

Research output: Contribution to journalArticle

Abstract

Aims: 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. Using in vitro and ex vivo studies on human tissues, we show that ROS accumulation 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 Angiotensin 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. Conclusion: sIncreased peak wall stress correlates with change in VSMC towards a synthetic phenotype mediated by ROS accumulation 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 dissection and rupture.

Original languageEnglish
Pages (from-to)316-324
Number of pages9
JournalCardiovascular Research
Volume100
Issue number2
DOIs
Publication statusPublished - Nov 1 2013

Keywords

  • CTGF
  • ROS
  • Thoracic aortic aneurysm
  • VSMC phenotype

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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    Branchetti, E., Poggio, P., Sainger, R., Shang, E., Grau, J. B., Jackson, B. M., Lai, E. K., Parmacek, M. S., Gorman, R. C., Gorman, J. H., Bavaria, J. E., & Ferrari, G. (2013). Oxidative stress modulates vascular smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm. Cardiovascular Research, 100(2), 316-324. https://doi.org/10.1093/cvr/cvt205