1056 Endothelial Cell-Specific MTORC1 Activation Promotes Cerebral Aneurysm Formation

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INTRODUCTION: Cerebral aneurysms affect up to 6–10 million individuals in the United States. Endothelial cell (EC) dysfunction is a key contributor to aneurysm formation and rupture. The mTORC1 pathway regulates EC proliferation, metabolism, and inflammatory signaling. Although inhibition of mTORC1 reduces aneurysm burden, the effect of EC-specific mTORC1 activation on aneurysm pathophysiology remains unclear. METHODS: We used a validated elastase-induced mouse model of cerebral aneurysm combined with systemic hypertension. Conditional EC-specific deletion of TSC1, a negative regulator of mTORC1, was achieved using tamoxifen-inducible VE-cadherin Cre-loxP technology. Four groups were studied: sham, wild-type aneurysm, TSC1 knockout with tamoxifen (mTORC1 activation), and TSC1 knockout without tamoxifen. Mice were sacrificed 28 days post-induction. Brains were harvested and perfused with blue gelatin for aneurysm visualization. Aneurysm formation and rupture were recorded. Histology, immunohistochemistry, and RT-PCR assessed EC dysfunction, apoptosis, inflammation, and remodeling markers. RESULTS: Rapamycin significantly reduced aneurysm progression (6/25 vs. 15/25; p = 0.012) without affecting formation rate (p = 0.73). Elastase-induced aneurysms showed vessel wall thinning, elastic lamina disruption, and EC death. Preliminary data from EC-specific mTORC1-activated mice suggest increased aneurysm rupture, upregulation of pro-inflammatory genes (e.g., IL-1β, VCAM-1, MMP9), decreased EC marker expression, increased apoptosis, and reduced proliferation. CONCLUSIONS: Endothelial mTORC1 activation plays a direct role in vascular dysfunction, inflammation, and aneurysm progression. These findings highlight a mechanistic role for EC signaling in aneurysm pathogenesis and suggest mTORC1 as a potential therapeutic target. Further investigation may support the development of pharmacologic strategies to prevent aneurysm rupture.

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