Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood-brain barrier.

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.