The Bilateral Ovariectomy in a Female Animal Exacerbates the Pathogenesis of an Intracranial Aneurysm

Mieko Oka,Haruka Miyata,Kampei Shimizu,Takakazu Kawamata,Tomohiro Aoki,Mika Kushamae,Isao Ono

doi:10.3390/brainsci10060335

Abstract

Considering the poor outcome of subarachnoid hemorrhage (SAH) due to the rupture of intracranial aneurysms (IA), mechanisms underlying the pathogenesis of IAs, especially the rupture of lesions, should be clarified. In the present study, a rat model of IAs in which induced lesions spontaneously ruptured resulting in SAH was used. In this model, the combination of the female sex and the bilateral ovariectomy increased the incidence of SAH, similar to epidemiological evidence in human cases. Importantly, unruptured IA lesions induced in female animals with bilateral ovariectomy were histopathologically similar to ruptured ones in the presence of vasa vasorum and the accumulation of abundant inflammatory cells, suggesting the exacerbation of the disease. The post-stenotic dilatation of the carotid artery was disturbed by the bilateral ovariectomy in female rats, which was restored by hormone replacement therapy. The in vivo study thus suggested the protective effect of estrogen from the ovary on endothelial cells loaded by wall shear stress. β-estradiol or dihydrotestosterone also suppressed the lipopolysaccharide-induced expression of pro-inflammatory genes in cultured macrophages and neutrophils. The results of the present study have thus provided new insights about the process regulating the progression of the disease.

Highlights

Considering the devastating outcome of subarachnoid hemorrhage (SAH) due to the rupture of an intracranial aneurysm (IA) [1,2], the development of a novel therapeutic strategy to prevent the rupture of intracranial aneurysms (IA) is mandatory for social health
In reference to established epidemiological evidence, the risk of SAH is higher in postmenopausal or older females than in males and in females before menopause [3,4,5,6,7,8], we first examined whether the sex difference in the incidence of SAH could be reproduced or not in a rat model of IAs [9] as in human cases, to escape many uncontrollable confounding factors
The presence of vasa vasorum with smooth muscle α-actin (SMA)-positive media, which we identified as a histopathological characteristic of ruptured IA lesions [9], could be detected even in unruptured lesions only from female animals with the bilateral ovariectomy, and not in female animals without ovariectomy or male animals (Figure 2e)

Summary

Introduction

Considering the devastating outcome of subarachnoid hemorrhage (SAH) due to the rupture of an intracranial aneurysm (IA) [1,2], the development of a novel therapeutic strategy to prevent the rupture of IAs is mandatory for social health. Mechanisms underlying the rupture of lesions should, be clarified. We attempted to find a cue from well-established epidemiological evidence. Epidemiological studies have consistently demonstrated a higher incidence of SAH in older females or postmenopausal females [3,4,5,6,7,8]. Based on the necessity of clarifying underlying mechanisms. Brain Sci. 2020, 10, 335; doi:10.3390/brainsci10060335 www.mdpi.com/journal/brainsci. Brain Sci. 2020, 10, 335 of the rupture of IAs, we examined whether sex difference is present, and if present, why, using the already-established animal model of IAs [9]

Methods

Results

Discussion

Conclusion