Sex-specific differences in basilar artery vasospasm after subarachnoid hemorrhage: evidence from a rabbit model

Abstract

Background – Subarachnoid hemorrhage (SAH) remains a devastating cerebrovascular disorder in which cerebral vasospasm is a key determinant of secondary injury and outcome. Sex differences are well-documented clinically, women exhibit a higher incidence of aneurysmal SAH and often worse outcomes, but whether biological sex influences vasospasm severity in controlled preclinical settings remains unclear. Methods – In a randomized, controlled rabbit model, we investigated sex-specific differences in basilar artery (BA) vasospasm after SAH. Twenty-four New Zealand White rabbits (12 male, 12 female) were allocated to Control, SHAM, or SAH groups. SAH was induced by cisterna magna injection of autologous blood; SHAM animals received saline. On Day 7, BA segments were harvested for quantitative assessment of vasospasm using the Vasospasm Index (VSI: wall area/lumen area) and blinded qualitative histopathological scoring of smooth muscle contraction, endothelial integrity, internal elastic membrane configuration, and adventitial thickness. Nonparametric statistical tests were used, with male vs. female comparison in SAH as the primary endpoint. Results – Control and SHAM animals showed no significant sex differences in VSI (Control: p = 0.47; SHAM: p = 0.06). In contrast, SAH induced severe vasospasm in males (VSI 2.34 ± 0.63) compared with moderate vasospasm in females (1.27 ± 0.49, p < 0.001). Histopathology corroborated these findings, with severe endothelial disruption and smooth muscle hypercontraction in males versus moderate alterations in females. Conclusion – Male rabbits exhibited significantly more severe vasospasm than females after SAH, despite human epidemiology suggesting greater vulnerability in women. These results demonstrate sex as a fundamental biological variable in SAH pathophysiology and underscore the need for mechanistic studies exploring hormonal, autonomic, and inflammatory mediators. Incorporating sex into experimental design may ultimately inform sex-specific therapeutic strategies for SAH.