Abstract Body: Background: Female gender is a well-established risk factor for intracranial aneurysms (IA), with women showing a 3:1 prevalence, 2:1 rupture risk, and higher aneurysm multiplicity. This risk has also been recapitulated in IA mouse models. While the ovaries-estrogen axis has been considered protective, it may not be the primary organ-hormone pair influencing IA pathogenesis. The uterus, through systemic release of vascular endothelial growth factor (VEGF) during the menstrual cycle, might play a central role in this pathway.

Methods: IAs were induced in C57Bl/6 mice through stereotactic injection of elastase into the basal cisterns and hypertension via deoxycorticosterone pellets and 1% NaCl water. We compared aneurysm rupture rates, formation, and symptom-free survival across different groups: hysterectomy vs. sham-surgery, VEGF-receptor antagonist Sunitinib vs. vehicle, anti-VEGF monoclonal antibody (mAb) vs. isotype control (rat anti-IgG2a), and anti-VEGF mAb vs. isotype control in hysterectomized mice. VEGF plasma levels were measured using a Mouse VEGF ELISA kit.

Results: Female mice had significantly higher plasma VEGF levels than males (46.0 pg/ml vs 27.8 pg/ml, p<0.001). Hysterectomized females had a lower rate of aneurysm formation (61% vs 94%, p=0.04) and longer symptom-free survival (p<0.01) compared to sham-operated females, though rupture rates were similar (75% vs 90%, p=0.56). Mice treated with Sunitinib showed lower aneurysm formation rates (45% vs 76%, p=0.04) and longer symptom-free survival (p=0.008), with no significant difference in rupture rates (72% vs 90%, p=0.32). Mice treated with anti-VEGF mAb had lower aneurysm formation rates (40% vs 60%, p=0.03) and longer symptom-free survival (p=0.02), with no significant difference in rupture rates (75% vs 83%, p=0.66). However, in hysterectomized mice the protective effect of anti-VEGF mAb was lost, showing no difference in formation rate (50 vs 50%, p=1), rupture rate (57% vs. 62%, p=1), or symptom free survival (p=0.65).

Conclusions: Female mice exhibited higher systemic VEGF levels than males. Hysterectomy, anti-VEGF mAb, and VEGF-R blockade with Sunitinib all resulted in reduced aneurysm formation and longer symptom-free survival. After removing the uterus, the protective effect of anti-VEGF mAb was no longer present. These findings suggest that the uterine-VEGF axis may be a promising therapeutic target and highly relevant in understanding the gender-associated risks of IA.