Mechanistic Target of Rapamycin Complex 1 Signaling Modulates Vascular Endothelial Function Through Reactive Oxygen Species

Abstract

Background The mechanistic target of rapamycin complex 1 (mTORC1) is an important intracellular energy sensor that regulates gene expression and protein synthesis through its downstream signaling components, the S6‐kinase and the ribosomal S6 protein. Recently, signaling arising from mTORC1 has been implicated in regulation of the cardiovascular system with implications for disease. Here, we examined the contribution of mTORC1 signaling to the regulation of vascular function. Methods and Results Activation of mTORC1 pathway in aortic rings with leucine or an adenoviral vector expressing a constitutively active S6‐kinase reduces endothelial‐dependent vasorelaxation in an mTORC1‐dependent manner without affecting smooth muscle relaxation responses. Moreover, activation of mTORC1 signaling in endothelial cells increases reactive oxygen species (ROS) generation and ROS gene expression resulting in a pro‐oxidant gene environment. Blockade of ROS signaling with Tempol restores endothelial function in vascular rings with increased mTORC1 activity indicating a crucial interaction between mTORC1 and ROS signaling. We then tested the role of nuclear factor‐κB transcriptional complex in connecting mTORC1 and ROS signaling in endothelial cells. Blockade of inhibitor of nuclear factor κ‐B kinase subunit β activity with BMS‐345541 prevented the increased ROS generation associated with increased mTORC1 activity in endothelial cells but did not improve vascular endothelial function in aortic rings with increased mTORC1 and ROS signaling. Conclusions These results implicate mTORC1 as a critical molecular signaling hub in the vascular endothelium in mediating vascular endothelial function through modulation of ROS signaling.