Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood–brain barrier
Abstract 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 fa...
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| Format: | Article |
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Nature Publishing Group
2025-01-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03229-2 |
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| author | Denian Wang Zhi Yang Pengfei Wu Qingyan Li Chunyan Yu Ying Yang Yuefan Du Mengwei Jiang Junpeng Ma |
| author_facet | Denian Wang Zhi Yang Pengfei Wu Qingyan Li Chunyan Yu Ying Yang Yuefan Du Mengwei Jiang Junpeng Ma |
| author_sort | Denian Wang |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-9c66e838c2594e76ab0bb82cd7f1c6ed |
| institution | Kabale University |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-9c66e838c2594e76ab0bb82cd7f1c6ed2025-01-19T12:39:39ZengNature Publishing GroupTranslational Psychiatry2158-31882025-01-0115111210.1038/s41398-025-03229-2Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood–brain barrierDenian Wang0Zhi Yang1Pengfei Wu2Qingyan Li3Chunyan Yu4Ying Yang5Yuefan Du6Mengwei Jiang7Junpeng Ma8Precision 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 UniversityDepartment of Nephrology, West China Hospital, Sichuan UniversityPrecision 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 UniversityPrecision 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 UniversityFrontiers Science Center for Disease-related Molecular Network, Laboratory of Omics Technology and Bioinformatics. West China Hospital, Sichuan UniversityPrecision 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 UniversityPrecision 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 UniversityPrecision 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 UniversityDepartment of Neurosurgery, West China Hospital of Sichuan UniversityAbstract 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.https://doi.org/10.1038/s41398-025-03229-2 |
| spellingShingle | Denian Wang Zhi Yang Pengfei Wu Qingyan Li Chunyan Yu Ying Yang Yuefan Du Mengwei Jiang Junpeng Ma Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood–brain barrier Translational Psychiatry |
| title | Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood–brain barrier |
| title_full | Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood–brain barrier |
| title_fullStr | Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood–brain barrier |
| title_full_unstemmed | Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood–brain barrier |
| title_short | Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood–brain barrier |
| title_sort | adrenomedullin 2 attenuates anxiety like behaviors by increasing igf ii in amygdala and re establishing blood brain barrier |
| url | https://doi.org/10.1038/s41398-025-03229-2 |
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