Endothelial glycocalyx degradation links post-traumatic stress disorder to cardiovascular dysfunction

Background

Post-traumatic stress disorder (PTSD) is associated with a significantly increased risk of cardiovascular disease; however, the biological mechanisms underlying this association remain incompletely understood [1]. Chronic exposure to stress leads to persistent dysregulation of neuroendocrine systems, particularly the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system, which in turn promotes systemic inflammation and oxidative stress [2]. These processes are increasingly recognised as key contributors to vascular dysfunction. The endothelial glycocalyx, a carbohydrate-rich layer covering the luminal surface of endothelial cells, plays a central role in maintaining vascular integrity by regulating nitric oxide bioavailability, vascular permeability, shear stress sensing, and anti-inflammatory signalling [3]. Disruption of the glycocalyx has been implicated in multiple cardiometabolic conditions and may represent a critical interface between psychological stress and cardiovascular pathology. However, its specific role in PTSD-related vascular impairment remains insufficiently characterised.

Aims

This study aimed to investigate endothelial glycocalyx degradation as a potential mechanistic pathway linking PTSD-related neurobiological alterations with cardiovascular risk, and to identify key inflammatory, oxidative, and endothelial mediators involved in this process.

Methods

A structured integrative analysis was conducted using peer-reviewed studies indexed in PubMed, Scopus, and Web of Science. Studies assessing inflammatory cytokines, oxidative stress markers, endothelial dysfunction, and glycocalyx integrity in PTSD or chronic stress models were included. Both clinical and experimental data were analysed. Quantitative trends were evaluated through comparative synthesis, focusing on biomarkers such as interleukin-6, tumour necrosis factor-α, reactive oxygen species, and syndecan-1. Where available, statistically significant differences between PTSD and control populations were extracted and compared. Additional mechanistic insights were derived from translational vascular studies investigating stress-induced endothelial injury.

Results

Across analysed studies (n=32), PTSD and chronic stress conditions were consistently associated with elevated inflammatory and oxidative stress markers. Interleukin-6 levels were increased by approximately 35–60% in PTSD populations compared to controls (p<0.01), while tumour necrosis factor-α showed a 25–40% elevation (p<0.05). Biomarkers of endothelial glycocalyx degradation, particularly circulating syndecan-1, demonstrated increases of up to 1.8-fold (p<0.01) in stress-exposed groups. These alterations were accompanied by reduced nitric oxide bioavailability, increased endothelial permeability, impaired endothelium-dependent vasodilation, and enhanced vascular stiffness. Mechanistically, sustained activation of neuroendocrine stress pathways promoted excessive production of reactive oxygen species, leading to activation of matrix metalloproteinases responsible for glycocalyx shedding. Furthermore, increased leukocyte adhesion, platelet activation, and a prothrombotic endothelial phenotype were observed. Although direct clinical evidence specifically examining glycocalyx integrity in PTSD remains limited, converging findings from related models strongly support its involvement.

Conclusions

Endothelial glycocalyx degradation represents a biologically plausible mechanism linking PTSD with increased cardiovascular risk. The interaction between neuroendocrine stress responses, inflammation, and endothelial dysfunction highlights the glycocalyx as a promising diagnostic and therapeutic target. Future research should prioritise longitudinal studies and validation of glycocalyx-associated biomarkers to improve early risk stratification and prevention of cardiovascular complications in PTSD populations

References

1. Padhi, B. K., Khatib, M. N., Serhan, H. A., Gaidhane, A. M., Rustagi, S., Zahiruddin, Q. S., Sharma, R. K., & Satapathy, P. (2024). Cardiovascular impact of post-traumatic stress disorder: A systematic review and meta-analysis. Current Problems in Cardiology, 49(8), 102632. https://doi.org/10.1016/j.cpcardiol.2024.102632
2. Gu, H.-F., Tang, C.-K., & Yang, Y.-Z. (2012). Psychological stress, immune response, and atherosclerosis. Atherosclerosis, 223(1), 69–77. https://doi.org/10.1016/j.atherosclerosis.2012.01.021
3. Foote, C. A., Soares, R. N., Ramirez-Perez, F. I., Ghiarone, T., Aroor, A., Manrique-Acevedo, C., Padilla, J., & Martinez-Lemus, L. (2022). Endothelial glycocalyx. Comprehensive Physiology, 12(4), 3781–3811. https://doi.org/10.1002/cphy.c210029