Pulse pressure-induced transmural fluid flux increases bovine aortic smooth muscle cell apoptosis in a mitogen activated protein kinase dependent manner.
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.
Birney
Yvonne A
YA
Vascular Health Research Centre, Faculty of Science and Health, Dublin City University, Dublin, Ireland.
Sweeney
Catherine H
CH
Cappadona
Charles R
CR
Sitzmann
James V
JV
Cummins
Philip M
PM
Redmond
Eileen M
EM
Cahill
Paul A
PA
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
D016895:Culture Media, Serum-Free; D019384:Nucleic Acid Synthesis Inhibitors; D003609:Dactinomycin; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D020169:Caspases