IGF-1 Inhibits the Hemodynamics‑Induced Progression of Intracranial Aneurysms by Modulating the Proliferation and Apoptosis of Vascular Smooth Muscle Cells.

Abnormal shear stress is closely linked to the progression of intracranial aneurysms (IAs) and the apoptosis of middle layer of vascular wall. Insulin-like growth factor-1 (IGF-1) is crucial for vascular protection by inhibiting local vascular cell apoptosis; however, its involvement in the pathology of IAs remains unclear. Eight human IAs and 8 superficial temporal artery (STA) samples were collected for high-throughput sequencing to analyze the expression of IGF-1. IA mouse models were established to evaluate the effect of IGF-1 on the aneurysmal remodeling of the cerebral arteries. We conducted a comprehensive analysis of the Circle of Willis in mice using pathological and proteomic methods to assess the proliferation and apoptosis of vascular smooth muscle cells (VSMCs). Additionally, vessel perfusion was perfomed to evaluate the incidence of IAs in mouse model. In vitro, mouse VSMCs and endothelial cells (ECs) of aorta were extracted, and a co-culture model with a flow chamber was established to simulate a laminar flow environment. The relationship between wall shear stress (WSS) gradient and the expression of IGF-1 was explored. Then the proliferation and apoptosis of VSMCs, and the related signaling pathway was determined by CCK8, flow cytometry, immunoblotting analysis and chromatin immunoprecipitation. Both IGF-1 and IGF-1R was downregulated in human IAs. High WSS reduced VSMC IGF-1 expression, facilitated apoptosis in VSMCs, and suppressed their proliferation. Over expression 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. High WSS downregulates the expression of IGF-1 in VSMCs, thereby inhibiting its proliferative and anti-apoptotic effects, which ultimately contributes to the IA progression via PI3K/AKT signaling pathway. Furthermore, FOXM1 played a role in this process by targeting IGF-1.