Regulation of YAP by Mammalian Target of Rapamycin Complex 1 in Endothelial Cells Controls Blood Pressure Through COX-2/mPGES-1/PGE2 Cascade

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

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Author(s)

  • Liu Yao
  • Jinlong He
  • Bochuan Li
  • Meng Yan
  • Hui Wang
  • Lu Tan
  • Mingming Liu
  • Xue Lv
  • Huizhen Lv
  • Xu Zhang
  • Chen Chen
  • Daowen Wang
  • Ying Yu
  • Yi Zhu
  • Ding Ai

Detail(s)

Original languageEnglish
Pages (from-to)936-946
Journal / PublicationHypertension
Volume74
Issue number4
Online published5 Aug 2019
Publication statusPublished - Oct 2019
Externally publishedYes

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 Tie-2-Cre-mediated regulatory associated protein of mTOR (mammalian target of rapamycin; Raptor) heterozygous-deficient (Tie2Cre-RaptorKD) mice than control mice both before and after Ang II infusion. Acetylcholine-evoked endothelium-dependent relaxation of mesenteric arteries was impaired in Tie2Cre-RaptorKD 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 Raptorflox/- mice to a similar extent as in Tie2Cre-RaptorKD mice. Metabolomic profiling revealed that the plasma content of prostaglandin E2 was reduced in Tie2Cre-RaptorKD mice with or without Ang II infusion. In endothelial cells, reduction of the protein level of YAP (yes-associated protein) with siRNA-mediated RPTOR 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 Tie2Cre-RaptorKD 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.

Research Area(s)

  • arachidonic acid, blood pressure, endothelium, hypertension, vessel relaxation

Citation Format(s)

Regulation of YAP by Mammalian Target of Rapamycin Complex 1 in Endothelial Cells Controls Blood Pressure Through COX-2/mPGES-1/PGE2 Cascade. / Yao, Liu; He, Jinlong; Li, Bochuan et al.
In: Hypertension, Vol. 74, No. 4, 10.2019, p. 936-946.

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review