Exacerbation of Intracranial Aneurysm and Aortic Dissection in Hypertensive Rat Treated With the Prostaglandin F–Receptor Antagonist AS604872

Miyuki Fukuda; Tomohiro Aoki; Toshiaki Manabe; Akiko Maekawa; Takayuki Shirakawa; Hiroharu Kataoka; Yasushi Takagi; Susumu Miyamoto; Shuh Narumiya

doi:10.1254/jphs.14148FP

Full Paper

Exacerbation of Intracranial Aneurysm and Aortic Dissection in Hypertensive Rat Treated With the Prostaglandin F–Receptor Antagonist AS604872

Miyuki Fukuda, Tomohiro Aoki, Toshiaki Manabe, Akiko Maekawa, Takayuki Shirakawa, Hiroharu Kataoka, Yasushi Takagi, Susumu Miyamoto, Shuh Narumiya

Author information

Miyuki Fukuda
Department of Neurosurgery, Medical Innovation Center, Kyoto University Graduate School of Medicine, Japan
Department of Pharmacology, Kyoto University Graduate School of Medicine, Japan
Core Research for Evolutional Science and Technology (CREST), Medical Innovation Center, Kyoto University Graduate School of Medicine, Japan
Tomohiro Aoki
Department of Pharmacology, Kyoto University Graduate School of Medicine, Japan
Core Research for Evolutional Science and Technology (CREST), Medical Innovation Center, Kyoto University Graduate School of Medicine, Japan
Innovation Center for Immunoregulatory Technologies and Drugs (AK project), Kyoto University Graduate School of Medicine, Japan
Toshiaki Manabe
Shiga Medical Center Research Institute, Japan
Akiko Maekawa
Innovation Center for Immunoregulatory Technologies and Drugs (AK project), Kyoto University Graduate School of Medicine, Japan
Takayuki Shirakawa
Department of Pharmacology, Kyoto University Graduate School of Medicine, Japan
Hiroharu Kataoka
Department of Neurosurgery, National Cerebral and Cardiovascular Center, Japan
Yasushi Takagi
Department of Neurosurgery, Medical Innovation Center, Kyoto University Graduate School of Medicine, Japan
Susumu Miyamoto
Department of Neurosurgery, Medical Innovation Center, Kyoto University Graduate School of Medicine, Japan
Shuh Narumiya
Department of Pharmacology, Kyoto University Graduate School of Medicine, Japan
Core Research for Evolutional Science and Technology (CREST), Medical Innovation Center, Kyoto University Graduate School of Medicine, Japan
Innovation Center for Immunoregulatory Technologies and Drugs (AK project), Kyoto University Graduate School of Medicine, Japan

Keywords: prostaglandin F₂α receptor (FP), AS604872, intracranial aneurysm, aortic dissection, chronic inflammation

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Supplementary material

2014 Volume 126 Issue 3 Pages 230-242

DOI https://doi.org/10.1254/jphs.14148FP

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Abstract

Intracranial aneurysm (IA) and aortic dissection are both complications of hypertension and characterized by degeneration of the media. Given the involvement of prostaglandin F₂α and its receptor, FP, in extracellular matrix remodeling in a mouse model of pulmonary fibrosis, here we induced hypertension and IA in rats by salt loading and hemi-lateral ligation of renal and carotid arteries and examined effects of a selective FP antagonist, AS604872, on these vascular events. AS604872 significantly accelerated degeneration of the media in both cerebral artery and aorta as evidenced by thinning of the media and disruption of the elastic lamina and promoted IA and aortic dissection. Notably, AS604872 induced expression of pro-inflammatory genes such as E-selectin in lesions and significantly enhanced macrophage infiltration. Suppression of surface expression of E-selectin with cimetidine prevented macrophage infiltration and aortic dissection. Thus, AS604872 exacerbates vascular inflammation in hypertensive rats and facilitates IA and aortic dissection. These results demonstrate that both IA and aortic dissection are caused by chronic inflammation of the arterial wall, which is worsened by AS604872, cautioning that other FP antagonists may share such deleterious actions in vascular homeostasis and suggesting that AS604872 can be used to make models of these vascular diseases with extensive degeneration.

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