Anxiety disorders are among the most prevalent mental health conditions globally, impacting millions of people. These conditions are characterized by overwhelming worry and fear that disrupt daily life. While many people experience occasional anxiety in response to stress, anxiety disorders occur when this fear becomes excessive and persistent, often leading to debilitating behaviors aimed at avoiding perceived threats. In fact, it is estimated that around 4% of the world’s population suffers from anxiety disorders, which significantly decrease quality of life and pose a substantial challenge to overall mental and physical health.
Given the widespread impact of anxiety, numerous treatment options have been developed over the years. These include medications (such as antidepressants and benzodiazepines) and various types of psychotherapy, with cognitive-behavioral therapy (CBT) being one of the most effective approaches. However, many existing treatments do not offer relief to all individuals, and side effects, as well as medication resistance, can hinder treatment success. This challenge has prompted neuroscientists to delve deeper into the underlying neurobiological mechanisms of anxiety disorders, with the goal of discovering novel therapeutic targets.
A growing area of research suggests that one such target may lie in the blood-brain barrier (BBB), a protective membrane that regulates what can and cannot pass from the bloodstream into the brain. Recent studies have uncovered a potential link between BBB dysfunction and the development of anxiety-like behaviors. While the exact nature of this connection remains unclear, scientists believe that improving the integrity of the BBB could provide new avenues for treating anxiety disorders.
The Blood-Brain Barrier: Its Role and Importance
The blood-brain barrier (BBB) is a specialized system of cells that forms a protective boundary between the bloodstream and the central nervous system (CNS), which includes the brain and spinal cord. Its primary role is to ensure that harmful substances in the bloodstream, such as toxins and pathogens, are prevented from entering the brain, while allowing essential nutrients and gases, such as oxygen, to pass through.
Interestingly, the BBB not only protects the brain from external harm but also regulates the flow of various molecules necessary for proper neural function, including neurotransmitters, hormones, and other signaling proteins. Therefore, any disruption or damage to the BBB can have far-reaching effects, potentially contributing to a variety of neurological and psychiatric disorders.
This insight into the crucial role of the BBB in brain health has led researchers to explore its association with anxiety disorders, as dysfunction of the BBB might allow unwanted substances to enter the brain, triggering inflammatory responses, impairing neural function, and exacerbating anxiety-related behaviors.
Research at Sichuan University: The Discovery of ADM2
A promising study at Sichuan University has taken an important step forward in understanding the relationship between BBB dysfunction and anxiety. Researchers focused on the role of an angiogenic growth factor, a type of molecule known to stimulate the formation of blood vessels. Specifically, the study identified adrenomedullin 2 (ADM2) as a potential agent capable of enhancing BBB integrity and reducing anxiety-like behaviors in mice.
The findings were published in the journal Translational Psychiatry and have spurred interest in the development of novel treatments aimed at boosting BBB function as a way of alleviating anxiety. According to lead researchers Denian Wang, Zhi Yang, and their team, the angiogenic growth factor ADM2 holds great potential for the treatment of anxiety-like behaviors linked to BBB damage.
In their study, the team conducted a range of experiments involving male mice with free movement and access to food and water. The mice underwent a variety of behavioral tests designed to assess different aspects of anxiety, including:
- Social interaction with other mice.
- Object recognition tasks to evaluate memory.
- Fear-conditioning tasks to test the fear response.
- T-maze tasks to examine decision-making in the face of potential threats.
- Open-field test and forced swim tasks to evaluate general anxiety.
- Tail suspension test, which gauges stress-induced immobility.
These tests were complemented by an array of cutting-edge experimental techniques, such as pharmacological, viral, biochemical, and optogenetic methods, designed to better understand the molecular and cellular mechanisms underlying the observed effects.
ADM2’s Role in BBB Integrity and Anxiety-Like Behavior
One of the most significant findings from the study was the discovery that ADM2 plays a key role in maintaining the integrity of the BBB, thus preventing the leakage of molecules that could contribute to anxiety. Specifically, the researchers found that the administration of ADM2 helped increase the levels of a protein called VE-cadherin—a crucial component of the endothelial cells that line blood vessels in the brain. VE-cadherin is essential for the proper formation and functioning of tight junctions between endothelial cells, which are vital for the selective permeability of the BBB.
Additionally, the researchers noticed that the expression of insulin-like growth factor 2 (IGF-II) was boosted when ADM2 was administered. IGF-II is a protein known to contribute to cellular growth and brain function. By enhancing IGF-II levels, ADM2 may protect against the breakdown of the BBB, allowing the brain to function optimally and reducing anxiety-like behaviors.
The researchers discovered that in the absence of ADM2, a group of ADM2 knockout mice displayed symptoms of anxiety-like behaviors, with evidence pointing to significant BBB dysfunction. This dysfunction was indicated by increased levels of Evans blue staining—an indicator of BBB leakage—and a reduction in VE-cadherin protein levels, both of which confirmed BBB damage.
In vitro studies further supported these findings, showing that the administration of ADM2 promoted VE-cadherin expression and decreased IGF-II leakage through the endothelial barrier, reinforcing its role in preserving BBB function and preventing the development of anxiety.
Implications for Anxiety Treatment
The findings from Sichuan University suggest that ADM2 could serve as a promising candidate for alleviating anxiety by enhancing the integrity of the blood-brain barrier. If further studies confirm these results, ADM2 may become a therapeutic target for anxiety treatments, especially in cases where BBB dysfunction is implicated in the disorder.
However, the road ahead is still long before ADM2 or similar molecules could be used in clinical settings. Before ADM2 can be considered as a viable therapeutic approach, researchers must validate the effects observed in mice, exploring its potential to mitigate anxiety in humans. Additionally, further investigation is necessary to understand the mechanisms by which ADM2 regulates BBB function and how it could be targeted effectively for therapeutic use without undesirable side effects.
Conclusion
In conclusion, the research conducted by Sichuan University offers valuable insights into the relationship between blood-brain barrier (BBB) integrity and anxiety disorders, highlighting a promising potential therapeutic approach through the growth factor ADM2. This study reveals that ADM2 may alleviate anxiety-like behaviors by strengthening the BBB and enhancing the levels of IGF-II, a protein crucial for brain function and cell growth. By restoring the protective barrier of the BBB, ADM2 helps prevent the leakage of harmful substances into the brain, which could contribute to anxiety. While these findings are promising, further research is needed to validate the effects of ADM2 in humans and explore its full potential as a treatment option for anxiety. As scientists continue to unravel the complex neurobiological mechanisms underlying anxiety, the development of targeted therapies like ADM2 may offer hope for better, more effective treatments for individuals suffering from anxiety disorders.
Reference: Denian Wang et al, Adrenomedullin 2 attenuates anxiety-like behaviors by increasing IGF-II in amygdala and re-establishing blood–brain barrier, Translational Psychiatry (2025). DOI: 10.1038/s41398-025-03229-2.