title: Pulse pressure-induced transmural fluid flux increases bovine aortic smooth muscle cell apoptosis in a mitogen activated protein kinase dependent manner.
abstract: BACKGROUND
  Mechanical forces associated with blood flow are critical in the regulation of vascular smooth muscle cell (VSMC) growth, migration, differentiation, and apoptosis as fundamental features in the pathogenesis of vascular disease. We investigated the effect of pulse pressure on VSMC apoptosis.
  
  
  METHODS
  Using a perfused transcapillary co-culture system, bovine thoracic aortic SMC (BASMC) were exposed to increases in pulsatile flow (0.3-17 ml/min) hence pulse pressure (amplitude of pulse 6-50 mmHg in the absence or presence of bovine aortic endothelial cells (BAEC). The extent of apoptosis was determined by measuring caspase-3 activity, the levels of pro- and anti-apoptotic Bcl-2 family proteins, FasL and cellular apoptosis susceptibility (CAS) protein expression and the extent of DNA fragmentation.
  
  
  RESULTS
  Changes in pulse pressure resulted in a significant force- and time-dependent increase in caspase-3 activity in BASMC. This effect was maximal after 6 h, independent of BAEC presence, and attenuated following inhibition of mitogen-activated protein kinase (MAPK) activity with PD98059. In parallel cultures, there was a significant increase in Bad and Bax expression, concomitant with an increase in DNA fragmentation, and a significant decrease in Bcl-2 and Bcl-XL expression. The pro-apoptotic effects of pulse pressure were specific differentiated cells but independent of p53, in as much as FasL and CAS expression were enhanced in differentiated adult but decrease in de-differentiated embryonic cells in response to flow.
  
  
  CONCLUSIONS
  These results suggest that pulse pressure promotes phenotypically distinct VSMC apoptosis in vitro in an endothelial-independent, MAPK-dependent, manner.
authors.affiliation: Vascular Health Research Centre, Faculty of Science and Health, Dublin City University, Dublin, Ireland.
authors.forename: Yvonne A
authors.initials: YA
authors.lastname: Birney
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Sweeney
authors.forename: Charles R
authors.initials: CR
authors.lastname: Cappadona
authors.forename: James V
authors.initials: JV
authors.lastname: Sitzmann
authors.forename: Philip M
authors.initials: PM
authors.lastname: Cummins
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Redmond
authors.forename: Paul A
authors.initials: PA
authors.lastname: Cahill
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D003609:Dactinomycin / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010641:Phenotype
chemical_list: D016895:Culture Media, Serum-Free; D019384:Nucleic Acid Synthesis Inhibitors; D003609:Dactinomycin; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D020169:Caspases