Anxiety disorders, marked by increased apprehension and dysfunctional avoidance behaviors in response to real or perceived threats, are among the most prevalent mental health conditions worldwide. These disorders affect an estimated 4% of the global population and significantly diminish the quality of life. Despite the availability of various therapeutic options, existing treatments often fail to provide relief for all individuals. This has driven neuroscientists to explore novel biological targets to address anxiety and its related behaviors more effectively.
A recent research has highlighted a potential link between anxiety disorders and dysfunction in the blood-brain barrier (BBB). The BBB, a protective layer formed by endothelial cells, serves as a critical regulator of substance exchange between the bloodstream and the brain. However, the precise mechanisms linking BBB dysfunction to anxiety remain unclear.
The study conducted by researchers at Sichuan University evaluated the role of an angiogenic growth factor in alleviating anxiety-like behaviors, with findings published in Translational Psychiatry. The research demonstrated that adrenomedullin 2 (ADM2) strengthens the blood-brain barrier (BBB) and reduces anxiety-like behaviors in mice. The study included a series of behavioral tests to assess anxiety-like and social behaviors, such as interactions with other mice, recognition of new objects, exploration of novel object positions, navigation of a T-shaped maze, fear conditioning, open-field tests, forced swimming, and tail suspension. To explore the mechanisms underlying BBB integrity and anxiety reduction, the team employed pharmacological, viral, biochemical, and optogenetic techniques to identify specific molecular and cellular factors influenced by ADM2.
The study found that ADM2 plays a crucial role in maintaining the integrity of the BBB. Transcriptome and biochemical analyses revealed that ADM2 enhances the expression of insulin-like growth factor 2 (IGF-II). IGF-II activation triggers the AKT-GSK3β-mTOR signaling pathway via the IGF-II receptor (IGF-IIR). This signaling cascade contributes to strengthening the BBB, as evidenced by decreased leakage of IGF-II and increased levels of VE-cadherin, a protein essential for endothelial cell junctions. Kim et al. highlighted how oxidative stress-induced BBB damage contributes to the development of anxiety-related behaviors. This study emphasized that the BBB’s integrity is crucial for preventing the infiltration of harmful substances into the brain, which can exacerbate neuroinflammation and anxiety. These findings underscore the centrality of the BBB in maintaining mental health and regulating anxiety.
In experiments involving ADM2 knockout mice, the researchers observed increased BBB dysfunction. This was demonstrated through elevated Evans blue staining, indicative of compromised BBB integrity, and reduced VE-cadherin levels. These mice also exhibited heightened anxiety-like behaviors, further linking BBB dysfunction to anxiety.
The study also explored ADM2’s effects in in vitro models, where it promoted VE-cadherin expression and reduced IGF-II leakage through endothelial barriers. By preserving IGF-II levels in the brain and enhancing BBB integrity, ADM2 appeared to alleviate anxiety-like behaviors and social deficits in the mice.
The findings suggest that ADM2 may be a promising therapeutic target for anxiety disorders by improving BBB function and regulating key proteins like IGF-II. While further studies are needed to validate its effects on humans and ensure safety, this research offers valuable insights into the link between BBB integrity and anxiety, paving the way for targeted treatments to benefit millions affected by these conditions.
References
- Wang D, Yang Z, Wu P, Li Q, Yu C, Yang Y, et al. Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood–brain barrier. Transl Psychiatry. 2025 Jan 14;15(1):1–12.
- Kim S, Jung UJ, Kim SR. Role of Oxidative Stress in Blood-Brain Barrier Disruption and Neurodegenerative Diseases. Antioxidants. 2024 Dec;13(12):1462.