IGF-1调控平滑肌细胞维持血管稳态在颅内动脉瘤发生发展中的作用及相关分子机制

Intracranial aneurysms (IAs) are described as "Untimed Bombs" in the brain. Previous study showed that it was closely related to altered blood vessel homeostasis caused by abnormal hemodynamics. Vascular smooth muscle cells (VSMCs) are the main cells that regulate the homeostasis of blood vessels, so abnormal hemodynamics will induce phenotypic changes of VSMCs to promote the occurrence of IA. IGF-1 (insulin-like growth factor -1) has been reported to inhibit the apoptosis and promote proliferation of VSMCs, leading to protect the blood vessels. We have found that IGF-1 and its upstream regulator FOXM1 were highly expressed at the early stage of the IA rabbit model, however, the role of IGF-1 in IA occurrence and development  remained to be clear. Therefore, in this project we plan to focus on the preventive and protective role of IGF-1 in IA occurrence and development. The main research will include: 1) animal study: exploring prevention and treatment effect of IGF-1 overexpression and interference on IA; 2) in vitro study: phenotypic maintenance effect of IGF-1 on VSMCs under stimulation of abnormal hemodynamics; confirmation of transcription regulation effect of FOXM1 on IGF-1. This study aims to elucidate the maintenance effect and mechanism of IGF-1 on vascular homeostasis induced by abnormal hemodynamics in the development of IA and provide new ideas for IA prevention and treatment strategies.

颅内动脉瘤（IA）被喻为脑内的“不定时炸弹”。研究表明其与异常血流动力学引起的血管稳态失调有密切关系。血管平滑肌细胞（VSMCs）是调节血管稳态的主要细胞，异常血流动力学刺激下会发生表型变化促进IA的发生。IGF-1（胰岛素样生长因子-1）被报道具有调节VSMCs的功能，从而对血管起保护作用。我们前期发现IGF-1及其上游调控因子FOXM1在IA模型初期显著高表达，但IGF-1在IA中的作用如何还尚待明确。因此，本项目拟围绕“IGF-1在IA的发生发展中起预防和保护作用”展开，包括：1）动物实验研究IGF-1的过表达和干扰对异常血流动力学诱导的IA的防治作用；2）体外研究VSMCs在异常血流动力学刺激下，IGF-1对其表型维持作用以及验证FOXM1对IGF-1的转录调控作用。本研究旨在阐明IGF-1对异常血流动力学诱导IA发生发展的血管稳态的维持作用以及机制，为IA的防治策略提供新的思路。

颅内血流动力学异常导致血管平滑肌细胞(vascular smooth muscle cells, VSMCs)过度凋亡并抑制其增殖，被认为是颅内动脉瘤(intracranial动脉瘤，IAs)形成和发展的重要原因。胰岛素样生长因子-1 (IGF-1)广泛参与血管保护过程，通过抑制凋亡作用，维持血管稳定，在颈动脉粥样硬化病变和腹主动脉瘤中均有相关研究。然而，IGF-1在保护脑血管防止IAs形成和发展方面的作用尚不清楚。本研究旨在阐明IGF-1对高wss诱导VSMCs下增殖和凋亡水平变化的影响，IGF-1对IAs形成和进展的作用及相关的信号通路。在本课题中，通过动物实验发现IGF-1干预后，其在IAs小鼠模型中的表达高于假手术组。同时，小鼠过表达IGF-1可抑制其颅底大血管的VSMCs的凋亡，促进VSMCs的增殖，从而抑制IAs的形成和发展。此外，在模拟颅内动脉瘤血流动力学的体外ECs-VSMCs共培养模型中发现，IGF-1可抑制高wss诱导的VSMCs异常增殖和凋亡。通过相关机制的研究发现，体外研究中，FOXM1正向调控IGF-1的表达，并通过PI3K/AKT通路促进VSMCs的增殖，并抑制凋亡。这些结果表明，IGF-1可能通过调控VSMCs的增殖和凋亡来维持血管稳定，从而抑制IAs的发生和发展。IAs具有高发病率、低破裂率和高致死致残率，既往手术干预均存在一定并发症和发生率，而药物治疗IAs一直是脑血管领域亟待解决的难题，本研究发现了潜在的IAs药物干预靶点，有望进一步发展动脉瘤治疗的新理念。