Exacerbation of intracranial aneurysm and aortic dissection in hypertensive rat treated with the prostaglandin F-receptor antagonist AS604872.

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.

• Authors: Miyuki Fukuda, Tomohiro Aoki, Toshiaki Manabe, Akiko Maekawa, Takayuki Shirakawa, Hiroharu Kataoka, Yasushi Takagi, Susumu Miyamoto, Shuh Narumiya
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 126 Issue 3 Pg. 230-42 ( 2014) ISSN: 1347-8648 [Electronic] Japan
• PMID: 25341845 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AS604872
• Biphenyl Compounds
• Fibrillar Collagens
• Inflammation Mediators
• Prostaglandin Antagonists
• Receptors, Prostaglandin
• Sodium Chloride, Dietary
• Sulfonamides
• prostaglandin F2alpha receptor

Topics

• Aortic Dissection (chemically induced, genetics, metabolism, pathology)
• Animals
• Aorta (drug effects, metabolism, pathology)
• Aortic Aneurysm (chemically induced, genetics, metabolism, pathology)
• Biphenyl Compounds (toxicity)
• Cerebral Arteries (drug effects, metabolism, pathology)
• Disease Models, Animal
• Fibrillar Collagens (metabolism)
• Humans
• Hypertension (complications, genetics, metabolism)
• Inflammation Mediators (metabolism)
• Intracranial Aneurysm (chemically induced, genetics, metabolism, pathology)
• Male
• Mice, Knockout
• Prostaglandin Antagonists (toxicity)
• Rats, Sprague-Dawley
• Receptors, Prostaglandin (antagonists & inhibitors, genetics, metabolism)
• Sodium Chloride, Dietary
• Sulfonamides (toxicity)
• Time Factors
• Vascular Remodeling (drug effects)
• Vasculitis (chemically induced, metabolism, pathology)