Molecular mechanism of endothelial growth arrest by laminar shear stress

This study was designed to elucidate the mechanism underlying the inhibitio n of endothelial cell growth by laminar shear stress. Tumor suppressor gene p53 was increased in bovine aortic endothelial cells subjected to 24 h of laminar shear stress at 3 dynes (1 dyne = 10 mu N)/cm(2) or higher, but not at 1.5 dynes/cm(2). One of the mechanisms of the shear-induced increase in p53 is its stabilization after phosphorylation by c-Jun N-terminal kinase. To investigate the consequence of the shear-induced p53 response, we found that prolonged laminar shear stress caused increases of the growth arrest proteins GADD45 (growth arrest and DNA damage inducible protein 45) and p21 (cip1), as well as a decrease in phosphorylation of the retinoblastoma gene product. Our results suggest that prolonged laminar shear stress causes a sustained p53 activation, which induces the up-regulation of GADD45 and p21 (cip1). The resulting inhibition of cyclin-dependent kinase and hypophospho rylation of retinoblastoma protein lead to endothelial cell cycle arrest. T his inhibition of endothelial cell proliferation by laminar shear stress ma y serve an important homeostatic function by preventing atherogenesis in th e straight part of the arterial tree that is constantly subjected to high l evers of laminar shearing.