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

J Pharmacol Sci. 2014;126(3):230-42. doi: 10.1254/jphs.14148fp. Epub 2014 Oct 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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