Strain-induced vascular endothelial cell proliferation requires PI3K-dependent mTOR-4E-BP1 signal pathway

The aim of this study was to determine whether the phosphatidylinositol 3- kinase ( PI3K)- dependent mammalian target of rapamycin ( mTOR)- eukaryotic initiation factor 4E binding protein 1 ( 4EBP1) signal pathway and S6 kinase ( S6K), the major element of the mTOR pathway, play a role in the enhanced vascular endothelial cell ( EC) proliferation induced by cyclic strain. Bovine aortic ECs were subjected to an average of 10% strain at a rate of 60 cycles/ min for <= 24 h. Cyclic strain- induced EC proliferation was reduced by pretreatment with rapamycin but not the MEK1 inhibitor PD- 98059. The PI3K inhibitors wortmannin and LY- 294002 also attenuated straininduced EC proliferation and strain- induced activation of S6K. Rapamycin but not PD- 98059 prevented strain- induced S6K activation, and PD- 98059 but not rapamycin prevented strain- induced activation of extracellular signal- regulated kinases 1 and 2. Cyclic strain also activated 4E- BP1, which could be inhibited by PI3K inhibitors. These data suggest that the PI3K- dependent S6K- mTOR- 4E- BP1 signal pathway may be critically involved in strain- induced bovine aortic EC proliferation.