Wang Denian, Yang Zhi, Wu Pengfei, Li Qingyan, Yu Chunyan, Yang Ying, Du Yuefan, Jiang Mengwei, Ma Junpeng
Precision Medicine Research Center, Precision Medicine Key Laboratory of Sichuan Province, State Key Laboratory of Respiratory Health and Multimorbidity, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Transl Psychiatry. 2025 Jan 14;15(1):10. doi: 10.1038/s41398-025-03229-2.
Anxiety disorder, a prevalent mental health issue, is one of the leading causes of disability worldwide. Damage to the blood-brain barrier (BBB) is implicated in anxiety, but its regulatory mechanisms remain unclear. Herein, we show that adrenomedullin 2 (ADM2), a novel angiogenic growth factor, alleviates autistic and anxiety-like behaviors in mice. Based on transcriptome analysis and biochemical analyses, we found that ADM2 facilitates the expression of insulin-like growth factor 2 (IGF-II), which then triggers the activation of the AKT-GSK3β-mTOR signaling pathway via the IGF-II receptor (IGF-IIR), rather than the IGF-I receptor (IGF-IR). Furthermore, as evidenced by increased Evans blue staining and decreased VE-cadherin levels, the BBB exhibited dysfunction in ADM2 knockout mice with anxiety-like behaviors. In in vitro studies, ADM2 administration promoted the expression of VE-cadherin and decreased IGF-II leakage through the endothelial barrier in a BBB model. Taken together, ADM2 may alleviate anxiety-like behavior and social deficits by enhancing BBB integrity and increasing IGF-II levels in the brain. These findings highlight the potential of ADM2 as a therapeutic target for anxiety and related mental disorders.
焦虑症是一种普遍存在的心理健康问题，是全球致残的主要原因之一。血脑屏障（BBB）受损与焦虑有关，但其调节机制尚不清楚。在此，我们表明肾上腺髓质素2（ADM2），一种新型血管生成生长因子，可减轻小鼠的自闭症和焦虑样行为。基于转录组分析和生化分析，我们发现ADM2促进胰岛素样生长因子2（IGF-II）的表达，然后通过IGF-II受体（IGF-IIR）而非IGF-I受体（IGF-IR）触发AKT-GSK3β-mTOR信号通路的激活。此外，伊文思蓝染色增加和VE-钙黏蛋白水平降低表明，在有焦虑样行为的ADM2基因敲除小鼠中，血脑屏障出现功能障碍。在体外研究中，在血脑屏障模型中给予ADM2可促进VE-钙黏蛋白的表达，并减少IGF-II通过内皮屏障的渗漏。综上所述，ADM2可能通过增强血脑屏障完整性和增加大脑中IGF-II水平来减轻焦虑样行为和社交缺陷。这些发现突出了ADM2作为焦虑症和相关精神障碍治疗靶点的潜力。
