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

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.

Non-invasive Diagnosis and Postoperative Evaluation of Carotid Artery Stenosis by BSA-Gd2O3 Nanoparticles-Based Magnetic Resonance Angiography

“…The neck skin was then sutured, and the surgical area was cleaned. 49 In Vivo MRA of Carotid Artery Stenosis. The rat brain was evaluated at 6 h after carotid artery stenosis was established using T1WI, T2WI, and DWI sequences based on a 9.4T BioSpec machine (Bruker, Germany).…”

“…Thereafter, the syringe needle was pulled out, and the artery was restored to its maximal partial lumen. The neck skin was then sutured, and the surgical area was cleaned …”

Prostanoids in Cardiac and Vascular Remodeling

“…Deletion of mPGES-1 globally 175 or in myeloid cells attenuates neointimal hyperplasia after vascular injury, 176 while deletion of mPGES-1 in vascular cells promotes the proliferative response. 176 Global deletion of EPr3 177 or deletion of EPr4 in VSMCs 178 or EPr4 agonists 179 restricts neointima formation in injured vessels. In contrast, global deletion of EPr2, 180 deletion of EPr4 in ECs, 179 and overexpression of EPr3 globally 177 or of EPr4 in VSMCs 178 promotes neointimal hyperplasia after vascular injury.…”

“…176 Global deletion of EPr3 177 or deletion of EPr4 in VSMCs 178 or EPr4 agonists 179 restricts neointima formation in injured vessels. In contrast, global deletion of EPr2, 180 deletion of EPr4 in ECs, 179 and overexpression of EPr3 globally 177 or of EPr4 in VSMCs 178 promotes neointimal hyperplasia after vascular injury. PGE 2 is also involved in vascular remodeling during aortic aneurysm (AAA) formation.…”

Spatiotemporal EP4-fibulin-1 expression is associated with vascular intimal hyperplasia

“…11 Tenascin-C has been implicated to play a role in VSMC proliferation and migration in vascular IH. 6, 9 However, a study using mPGES-1–deficient mice raises the possibility that other ECMs, besides tenascin-C, contribute to VSMC-mediated IH. 6 It has also been demonstrated that EP4 promotes physiological IH during development via ECM production, including the glycoprotein fibulin-1 and hyaluronic acid.…”