Sex and Genetic Background Effects on the Outcome of Experimental Intracranial Aneurysms.
Sex and Genetic Background Effects on the Outcome of Experimental Intracranial Aneurysms.
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DOI：
10.1161/strokeaha.120.029651
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发表时间：
2020-10
期刊：
影响因子：
8.3
通讯作者：
Ayata C
中科院分区：
文献类型：
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作者：
Yanagisawa T;Zhang H;Suzuki T;Kamio Y;Takizawa T;Morais A;Chung DY;Qin T;Murayama Y;Faber JE;Patel AB;Ayata C
颅内动脉瘤的形成和破裂风险在一定程度上由遗传因素和性别决定。为了检验它们的作用，我们比较了脑血管研究中常用的三个小鼠品系在颅内动脉瘤形成和破裂模型中的作用。以CD1、C57和129Sv雄性小鼠为模型，采用颅底立体定向注射弹性蛋白酶联合全身脱氧皮质酮-醋酸盐高血压的方法建立颅内动脉瘤模型。记录神经功能缺陷和死亡率。无论是在动物自然死亡后，还是在动物存活7-21天后，都在死后对动脉瘤和蛛网膜下腔出血分级进行量化。在不同的队列中，我们通过定量RT-PCR检测促炎介质，通过股动脉检测动脉血压，通过血管内乳胶铸型检测Willis环。我们发现，在动脉瘤形成、破裂和破裂后存活率方面，各组之间存在显著差异。129Sv小鼠的动脉瘤破裂发生率最高(80%)，其次是C57雌性(36%)、C57雄性(27%)和CD1(21%)。动脉瘤破裂的风险和未破裂动脉瘤的存在在所有三种菌株之间以及在男性和女性C57之间存在显著差异。对总体生存率和无赤字生存率进行Kaplan-Meier分析时，观察到了相同的等级。129Sv组蛛网膜下腔出血分级也较重。CD1小鼠表现出对动脉瘤破裂的最高抵抗力和最温和的结局。较高的平均血压和129Sv的Willis解剖环的主要表型差异为更高的发生率和更严重的动脉瘤破裂提供了解释。肿瘤坏死因子α、白介素1β和CCL2的表达在不同组间无差异。弹力酶诱导的小鼠颅内动脉瘤形成和破裂的结局取决于遗传背景，并表现出性别二型性。在颅内动脉瘤形成和自发性破裂的弹性酶模型中(左上和左中)，临床相关的终点(右上和右中)取决于小鼠的遗传背景和性别差异，如在患者中所见(a：正常；b：未破裂的动脉瘤；c：孤立的脑内出血；d，e：蛛网膜下腔出血1级和2级)。手稿中提出的进一步证据支持弹性蛋白酶模型和机制与血压和Willis环的解剖弱点有关的翻译相关性。
Intracranial aneurysm formation and rupture risk are in part determined by genetic factors and sex. To examine their role, we compared three mouse strains commonly used in cerebrovascular studies in a model of intracranial aneurysm formation and rupture. Intracranial aneurysms were induced in male CD1, male and female C57, and male 129Sv mice by stereotaxic injection of elastase at the skull base, combined with systemic deoxycorticosterone acetate-salt hypertension. Neurological deficits and mortality were recorded. Aneurysms and subarachnoid hemorrhage grades were quantified postmortem, either after spontaneous mortality or at 7–21 days if the animals survived. In separate cohorts, we examined pro-inflammatory mediators by quantitative RT-PCR, arterial blood pressure via the femoral artery, and the circle of Willis by intravascular latex casting. We found striking differences in aneurysm formation, rupture and post-rupture survival rates among the groups. 129Sv mice showed the highest rates of aneurysm rupture (80%), followed by C57 female (36%), C57 male (27%), and CD1 (21%). The risk of aneurysm rupture and the presence of unruptured aneurysms significantly differed among all three strains, as well as between male and female C57. The same hierarchy was observed upon Kaplan–Meier analysis of both overall survival and deficit-free survival. Subarachnoid hemorrhage grades were also more severe in 129Sv. CD1 mice showed the highest resistance to aneurysm rupture and the mildest outcomes. Higher mean blood pressures and the major phenotypic difference in the circle of Willis anatomy in 129Sv provided an explanation for the higher incidence of and more severe aneurysm ruptures. TNFα, IL-1β and CCL2 expressions did not differ among the groups. The outcome of elastase-induced intracranial aneurysm formation and rupture in mice depends on genetic background and shows sexual dimorphism. In an elastase model of intracranial aneurysm formation and spontaneous rupture (upper and middle left), clinically relevant endpoints (upper and middle right) depend on murine genetic background and sex difference, as seen in patients (a: normal; b: unruptured aneurysm; c: isolated intracerebral hemorrhage; d, e: subarachnoid hemorrhage Grades 1 and 2). Further evidence presented in the manuscript supports the translational relevance of the elastase model and mechanisms in relation to blood pressure and anatomical weaknesses in the circle of Willis.