VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure

Hu Xu, Shengnan Du, Bingying Fang, Chaojie Li, Xiao Jia, Senfeng Zheng, Sailun Wang, Qingwei Li, Wen Su, Nanping Wang, Feng Zheng, Lihong Chen, Xiaoyan Zhang, Jan Ake Gustafsson, Youfei Guan

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Prostaglandin E2 (PGE2) plays an important role in vascular homeostasis. Its receptor, E-prostanoid receptor 4 (EP4) is essential for physiological remodeling of the ductus arteriosus (DA). However, the role of EP4 in pathological vascular remodeling remains largely unknown. We found that chronic angiotensin II (AngII) infusion of mice with vascular smooth muscle cell (VSMC)specific EP4 gene knockout (VSMC-EP4/) frequently developed aortic dissection (AD) with severe elastic fiber degradation and VSMC dedifferentiation. AngII-infused VSMC-EP4/ mice also displayed more profound vascular inflammation with increased monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, matrix metalloproteinase-2 and - 9 (MMP2/9) levels, NADPH oxidase 1 (NOX1) activity, and reactive oxygen species production. In addition, VSMC-EP4/ mice exhibited higher blood pressure under basal and AngII-infused conditions. Ex vivo and in vitro studies further revealed that VSMC-specific EP4 gene deficiency significantly increased AngII-elicited vasoconstriction of the mesenteric artery, likely by stimulating intracellular calcium release in VSMCs. Furthermore, EP4 gene ablation and EP4 blockade in cultured VSMCs were associated with a significant increase in MCP-1 and NOX1 expression and a marked reduction in α-SM actin (α-SMA), SM22α, and SM differentiation marker genes myosin heavy chain (SMMHC) levels and serum response factor (SRF) transcriptional activity. To summarize, the present study demonstrates that VSMC EP4 is critical for vascular homeostasis, and its dysfunction exacerbates AngII-induced pathological vascular remodeling. EP4 may therefore represent a potential therapeutic target for the treatment of AD.

Original languageEnglish (US)
Pages (from-to)8457-8462
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number17
DOIs
StatePublished - 2019

Keywords

  • EP4
  • Hypertension
  • Inflammation
  • PGE2
  • Vascular remodeling

ASJC Scopus subject areas

  • General

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