The Prostaglandin E2 Receptor EP4 Promotes Vascular Neointimal Hyperplasia through Translational Control of Tenascin C via the cAPM/PKA/mTORC1/rpS6 Pathway

Cells. 2022 Aug 31;11(17):2720. doi: 10.3390/cells11172720.

Abstract

Prostaglandin E2 (PGE2) is an important metabolite of arachidonic acid which plays a crucial role in vascular physiology and pathophysiology via its four receptors (EP1-4). However, the role of vascular smooth muscle cell (VSMC) EP4 in neointimal hyperplasia is largely unknown. Here we showed that VSMC-specific deletion of EP4 (VSMC-EP4) ameliorated, while VSMC-specific overexpression of human EP4 promoted, neointimal hyperplasia in mice subjected to femoral artery wire injury or carotid artery ligation. In vitro studies revealed that pharmacological activation of EP4 promoted, whereas inhibition of EP4 suppressed, proliferation and migration of primary-cultured VSMCs. Mechanically, EP4 significantly increased the protein expression of tenascin C (TN-C), a pro-proliferative and pro-migratory extracellular matrix protein, at the translational level. Knockdown of TN-C markedly suppressed EP4 agonist-induced VSMC proliferation and migration. Further studies uncovered that EP4 upregulated TN-C protein expression via the PKA/mTORC1/Ribosomal protein S6 (rpS6) pathway. Together, our findings demonstrate that VSMC EP4 increases TN-C protein expression to promote neointimal hyperplasia via the PKA-mTORC1-rpS6 pathway. Therefore, VSMC EP4 may represent a potential therapeutic target for vascular restenosis.

Keywords: EP4; gene knockout; prostanoid; tenascin C; vascular stenosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dinoprostone* / metabolism
  • Extracellular Matrix Proteins / metabolism
  • Humans
  • Hyperplasia* / metabolism
  • Hyperplasia* / pathology
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Muscle, Smooth, Vascular / metabolism
  • Neointima / metabolism
  • Receptors, Prostaglandin E, EP4 Subtype* / metabolism
  • Ribosomal Protein S6 / metabolism
  • Tenascin* / metabolism
  • Vascular System Injuries*

Substances

  • Extracellular Matrix Proteins
  • Receptors, Prostaglandin E, EP4 Subtype
  • Ribosomal Protein S6
  • Tenascin
  • Mechanistic Target of Rapamycin Complex 1
  • Cyclic AMP-Dependent Protein Kinases
  • Dinoprostone

Grants and funding

This work was financially supported by the National Natural Science Foundation of China (Nos. 91639201, 81900267, 81970595, 81970606) and National Key R&D Program of China (No. 2020YFC2005000).