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

Departments of Surgery, Yale University School of Medicine, New Haven, and Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut Submitted 26 April 2004 ; accepted in final form 1 December 2004 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 (4E-BP1) 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 strain-induced 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. phosphatidylinositol 3-kinase; mammalian target of rapamycin; mitogen-activated protein; S6; signal transduction; eukaryotic initiation factor binding protein; Akt Address for reprint requests and other correspondence: B. E Sumpio, Dept. of Surgery, Yale Univ. School of Medicine, 333 Cedar St., New Haven, CT 06520 (E-mail: bauer.sumpio{at}yale.edu )