IGF-1 inhibits intracranial aneurysm progression by modulating VSMC proliferation and apoptosis

Intracranial aneurysms (IAs) are dangerous cerebrovascular lesions, with rupture leading to subarachnoid hemorrhage, a severe form of stroke. Abnormal wall shear stress (WSS) is a critical factor in IA progression, often linked to the apoptosis of vascular smooth muscle cells (VSMCs) in the middle layer of the arterial wall. While Insulin-like growth factor-1 (IGF-1) is recognized for its vascular protective effects, particularly in inhibiting local vascular cell apoptosis, its specific role in the complex pathology of IAs has remained largely undefined, representing a significant gap in understanding potential therapeutic targets.

Researchers collected 8 human intracranial aneurysm (IA) samples and 8 superficial temporal artery (STA) samples for high-throughput sequencing to analyze IGF-1 expression. Mouse models of IA were established to assess the impact of IGF-1 on aneurysmal remodeling. The Circle of Willis in mice was analyzed using pathological and proteomic methods to evaluate VSMC proliferation and apoptosis. Vessel perfusion was performed to determine IA incidence. In vitro, mouse VSMCs and aortic endothelial cells (ECs) were co-cultured in a flow chamber to simulate laminar flow, exploring the relationship between WSS gradient and IGF-1 expression. VSMC proliferation and apoptosis, and related signaling pathways, were determined by CCK8, flow cytometry, immunoblotting analysis, and chromatin immunoprecipitation.

Both IGF-1 and its receptor, IGF-1R, were significantly downregulated in the 8 human IA samples compared to control STAs. In vitro, high WSS reduced VSMC IGF-1 expression, facilitated VSMC apoptosis, and suppressed their proliferation. Overexpression of IGF-1 promoted VSMC proliferation and inhibited apoptosis both in vivo and in vitro. Moreover, increased IGF-1 expression reduced mouse IA incidence. Mechanistically, IGF-1 regulated high WSS-induced apoptosis and proliferation of VSMCs via the PI3K/AKT signaling pathway. Furthermore, elevated WSS was found to suppress the expression of FOXM1, which subsequently modulates the expression of IGF-1. This suggests a cascade where high WSS downregulates FOXM1, leading to reduced IGF-1, impaired VSMC health, and aneurysm progression.

IGF-1 overexpression significantly reduced the incidence of intracranial aneurysms in mouse models, highlighting its protective role.