Regulation of YAP by Mammalian Target of Rapamycin Complex 1 in Endothelial Cells Controls Blood Pressure Through COX-2/mPGES-1/PGE ₂ Cascade

Abstract

Endothelial cells regulate vascular tone by producing both relaxing and contracting factors to control the local blood flow. Hypertension is a common side effect of mTORC1 (mammalian target of rapamycin complex 1) inhibitors. However, the role of endothelial mTORC1 in hypertension remains elusive. The present study aimed to determine the role of endothelial mTORC1 in Ang II (angiotensin II)-induced hypertension and the underlying mechanism. Endothelial mTORC1 activity was increased by Ang II both in vitro and in vivo. Blood pressure was higher in <i>Tie-2-Cre</i>-mediated regulatory associated protein of mTOR (mammalian target of rapamycin; <i>Raptor</i>) heterozygous-deficient (<i>Tie2Cre-Raptor</i>^<i>KD</i>) mice than control mice both before and after Ang II infusion. Acetylcholine-evoked endothelium-dependent relaxation of mesenteric arteries was impaired in <i>Tie2Cre-Raptor</i>^<i>KD</i> mice. Treatment with indomethacin or a specific COX (cyclooxygenase)-2 inhibitor, NS-398, but not L-NG-nitroarginine methyl ester reduced endothelium-dependent relaxation in <i>Raptor</i>^{<i>flox</i>/-} mice to a similar extent as in <i>Tie2Cre-Raptor</i>^<i>KD</i> mice. Metabolomic profiling revealed that the plasma content of prostaglandin E₂ was reduced in <i>Tie2Cre-Raptor</i>^<i>KD</i> mice with or without Ang II infusion. In endothelial cells, reduction of the protein level of YAP (yes-associated protein) with <i>siRNA</i>-mediated <i>RPTOR</i> deficiency was autophagy dependent and transcriptionally regulated the expression of COX-2 and mPGES-1 (microsomal prostaglandin E synthase-1). Hence, overexpression of YAP in endothelial cells enhanced the mRNA and protein levels of COX-2 and mPGES-1 and reversed the endothelial dysfunction and hypertension in <i>Tie2Cre-Raptor</i>^<i>KD</i> mice. The present results demonstrate that suppression of mTORC1 activity in endothelial cells reduces prostaglandin E₂ production and causes hypertension by reducing YAP-mediated COX-2/mPGES-1 expression.