Sex and Genetic Background Effects on the Outcome of Experimental Intracranial Aneurysms

Abstract

Background and Purpose: Intracranial aneurysm formation and rupture risk are, in part, determined by genetic factors and sex. To examine their role, we compared 3 mouse strains commonly used in cerebrovascular studies in a model of intracranial aneurysm formation and rupture. Methods: Intracranial aneurysms were induced in male CD1 (Crl:CD1[ICR]), male and female C57 (C57BL/6NCrl), and male 129Sv (129S2/SvPasCrl or 129S1/SvImJ) 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 to 21 days if the animals survived. In separate cohorts, we examined proinflammatory mediators by quantitative reverse transcriptase–polymerase chain reaction, arterial blood pressure via the femoral artery, and the circle of Willis by intravascular latex casting. Results: We found striking differences in aneurysm formation, rupture, and postrupture 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 3 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 (tumor necrosis factor-alpha), IL-1β (interleukin-1-beta), and CCL2 (chemokine C-C motif ligand 2) expressions did not differ among the groups. Conclusions: The outcome of elastase-induced intracranial aneurysm formation and rupture in mice depends on genetic background and shows sexual dimorphism.