Shear stress‐dependent modulation of mTOR signaling in the endothelium of aged vessels

To test the hypothesis that shear stress retards endothelial senescence via attenuation of mTOR signaling, first‐order mesenteric arteries of 24‐month‐old rats were isolated, cannulated and pressurized (60mmHg) in vessel culture chambers. Vessels were subjected to 10 (normal shear stress, NS) or 20 dyne/cm 2 (high shear stress, HS) of shear stress for 5 days. Then, endothelial proteins were obtained, followed by western blot analysis. We found that HS did not affect protein expression of mTOR, but inhibited mTOR activity, as indicated by a reduction of phospho‐mTOR (Ser2448). This result was associated with reduced phosphorylation of p70S6 Kinase (Thr389) and S6 ribosomal protein (Ser235/236), downstream targets of mTOR. AMPK phosphorylation, which is reduced in response to aging, was also increased in HS vessels. As a result of HS, telomerase activity, a reduction of which is associated with an increased endothelial senescence, was increased. Incubation of NS vessels with AICAR (5×10 −4 M), an activator of AMPK, also increased telomerase activity. These data suggest that stimulation by shear stress prevents/delays endothelial senescence via suppressing vascular mTOR signaling and activating AMPK‐dependent pathways in aged vessels. (Supported by NIH grants HL43023 and HL070653).