Oka Mieko, Ono Isao, Shimizu Kampei, Kushamae Mika, Miyata Haruka, Kawamata Takakazu, Aoki Tomohiro
Department of Molecular Pharmacology, Research Institute, National Cerebral and Cardiovascular Center, Osaka 564-8565, Japan.
Core Research for Evolutional Science and Technology (CREST) from Japan Agency for Medical Research and Development (AMED), National Cerebral and Cardiovascular Center, Osaka 564-8565, Japan.
Brain Sci. 2020 May 31;10(6):335. doi: 10.3390/brainsci10060335.
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. -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.
考虑到颅内动脉瘤（IA）破裂导致蛛网膜下腔出血（SAH）的预后较差，IA发病机制，尤其是病变破裂的机制应予以阐明。在本研究中，使用了一种IA大鼠模型，其中诱导的病变会自发破裂导致SAH。在该模型中，雌性与双侧卵巢切除术的组合增加了SAH的发生率，这与人类病例的流行病学证据相似。重要的是，在双侧卵巢切除的雌性动物中诱导的未破裂IA病变在组织病理学上与存在血管滋养管和大量炎性细胞积聚的破裂病变相似，提示疾病加重。雌性大鼠的双侧卵巢切除术干扰了颈动脉狭窄后扩张，而激素替代疗法可使其恢复。因此，体内研究提示来自卵巢的雌激素对承受壁面剪应力的内皮细胞具有保护作用。β-雌二醇或二氢睾酮也抑制培养的巨噬细胞和中性粒细胞中脂多糖诱导的促炎基因表达。本研究结果因此为疾病进展调控过程提供了新见解。
