Excessive EP4 Signaling in Smooth Muscle Cells Induces Abdominal Aortic Aneurysm by Amplifying Inflammation

Taro Hiromi, Utako Yokoyama, Daisuke Kurotaki, Al Mamun, Ryo Ishiwata, Yasuhiro Ichikawa, Hiroshi Nishihara, Masanari Umemura, Takayuki Fujita, Shota Yasuda, Tomoyuki Minami, Motohiko Goda, Keiji Uchida, Shinichi Suzuki, Ichiro Takeuchi, Munetaka Masuda, Richard M. Breyer, Tomohiko Tamura, Yoshihiro Ishikawa

Research output: Contribution to journalArticle

Abstract

Objective: Excessive prostaglandin E2 production is a hallmark of abdominal aortic aneurysm (AAA). Enhanced expression of prostaglandin E2 receptor EP4 (prostaglandin E receptor 4) in vascular smooth muscle cells (VSMCs) has been demonstrated in human AAAs. Although moderate expression of EP4 contributes to vascular homeostasis, the roles of excessive EP4 in vascular pathology remain uncertain. We aimed to investigate whether EP4 overexpression in VSMCs exacerbates AAAs. Approach and Results: We constructed mice with EP4 overexpressed selectively in VSMCs under an SM22α promoter (EP4-Tg). Most EP4-Tg mice died within 2 weeks of Ang II (angiotensin II) infusion due to AAA, while nontransgenic mice given Ang II displayed no overt phenotype. EP4-Tg developed much larger AAAs than nontransgenic mice after periaortic CaCl2 application. In contrast, EP4fl/+;SM22-Cre;ApoE-/- and EP4fl/+;SM22-Cre mice, which are EP4 heterozygous knockout in VSMCs, rarely exhibited AAA after Ang II or CaCl2 treatment, respectively. In Ang II-infused EP4-Tg aorta, Ly6Chi inflammatory monocyte/macrophage infiltration and MMP-9 (matrix metalloprotease-9) activation were enhanced. An unbiased analysis revealed that EP4 stimulation positively regulated the genes binding cytokine receptors in VSMCs, in which IL (interleukin)-6 was the most strongly upregulated. In VSMCs of EP4-Tg and human AAAs, EP4 stimulation caused marked IL-6 production via TAK1 (transforming growth factor-β-activated kinase 1), NF-κB (nuclear factor-kappa B), JNK (c-Jun N-terminal kinase), and p38. Inhibition of IL-6 prevented Ang II-induced AAA formation in EP4-Tg. In addition, EP4 stimulation decreased elastin/collagen cross-linking protein LOX (lysyl oxidase) in both human and mouse VSMCs. Conclusions: Dysregulated EP4 overexpression in VSMCs promotes inflammatory monocyte/macrophage infiltration and attenuates elastin/collagen fiber formation, leading to AAA exacerbation.

Original languageEnglish
Pages (from-to)1559-1573
Number of pages15
JournalArteriosclerosis, Thrombosis, and Vascular Biology
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • aneurysm
  • angiotensin II
  • elastin
  • interleukin-6
  • signal transduction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Hiromi, T., Yokoyama, U., Kurotaki, D., Mamun, A., Ishiwata, R., Ichikawa, Y., Nishihara, H., Umemura, M., Fujita, T., Yasuda, S., Minami, T., Goda, M., Uchida, K., Suzuki, S., Takeuchi, I., Masuda, M., Breyer, R. M., Tamura, T., & Ishikawa, Y. (Accepted/In press). Excessive EP4 Signaling in Smooth Muscle Cells Induces Abdominal Aortic Aneurysm by Amplifying Inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology, 1559-1573. https://doi.org/10.1161/ATVBAHA.120.314297