title: Oxidative stress modulates vascular smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Increased 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.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Perelman School of Medicine at University of Pennsylvania, Children's Hospital of Philadelphia, Abramson Research Building, Suite 702E, 3615 Civic Center Blvd, Philadelphia, PA 19104-4318, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Branchetti
authors.forename: Paolo
authors.initials: P
authors.lastname: Poggio
authors.forename: Rachana
authors.initials: R
authors.lastname: Sainger
authors.forename: Eric
authors.initials: E
authors.lastname: Shang
authors.forename: Juan B
authors.initials: JB
authors.lastname: Grau
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Jackson
authors.forename: Eric K
authors.initials: EK
authors.lastname: Lai
authors.forename: Michael S
authors.initials: MS
authors.lastname: Parmacek
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gorman
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Gorman
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Bavaria
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ferrari
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000378:metabolism*; D055513:Connective Tissue Growth Factor / Q000502:physiology*; D020342:Finite Element Analysis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D018384:Oxidative Stress; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D026362:Serum Response Factor / Q000032:analysis; D014746:Vimentin / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000032:analysis
chemical_list: D017382:Reactive Oxygen Species; D026362:Serum Response Factor; D014746:Vimentin; D050807:ets-Domain Protein Elk-1; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor
keywords: CTGF; ROS; Thoracic aortic aneurysm; VSMC phenotype