Abstract Body: Background: Platelets form aneurysmal thrombi at the diseased aortic wall, where activation-dependent α-granule release is proposed to affect abdominal aortic aneurysm (AAA). NBEAL2 is required for α-granule biogenesis, and its deficiency causes marked loss of soluble cargo. While platelet activation is implicated in AAA progression, the role of secretion in aneurysm development/stability is poorly defined. We tested whether NBEAL2 loss alters AAA outcomes in a hypercholesterolemic angiotensin II (AngII) model.

Methods and Results: Male and female wildtype (WT) and Nbeal2^-/- mice (MMRRC- 031611-UCD) received a PCSK9 gain-of-function AAV followed by Western diet, and infused with AngII for 28 days (2 weeks after AAV injection). Body weight and plasma cholesterol were comparable between genotypes in both sexes, with cholesterol remaining markedly elevated throughout the study. Hematology confirmed macrothrombocytopenia in Nbeal2^-/- males and females. Loss of NBEAL2 profoundly augmented aneurysm pathology, manifesting as a marked increase in rupture. Male Nbeal2^-/- mice exhibited ~90% mortality (10/11), with most deaths occurring within the first 10 days of AngII infusion, indicating early aneurysm destabilization. In contrast, WT males showed substantially lower mortality over the same period (4/13). Notably, NBEAL2 deficiency also unmasked susceptibility in females, a group typically protected from AngII-induced AAA. While WT females maintained complete survival, Nbeal2^-/- females developed significant pathology, with ~40% mortality (5/12) by day 28 and a delayed onset of rupture events. This shift to vulnerability indicates that platelet α-granule release directly affects sex-based protection. Necropsy consistently identified hemoperitoneum or hemothorax, confirming aneurysm rupture as the cause of death. Under basal saline infused conditions, ex vivo aortic diameters did not differ between WT and Nbeal2^-/- mice, demonstrating that NBEAL2 deficiency may amplify pathological instability rather than baseline aortic structure.

Conclusion: NBEAL2-dependent platelet α-granule biogenesis protects against AngII-induced aneurysm rupture in both sexes, supporting a stabilizing role for platelet granule pathways in aneurysm containment.