An animal model of endometriosis reveals stress related disturbed vitamin D - vitamin D receptor axis

Promising animal model of endometriosis in rodents yield new results

Key Points

Highlights:

• The negative impact of stress on endometriosis known previously was clarified by new data in this existing model, suggests that this could be through macrophage recruitment, cytokine changes, and a potentially unsettled Vitamin D: Vitamin D receptor action. 

Importance:

• Both eutopic and ectopic endometrium express the vitamin D receptor, and Vitamin D signaling through this receptor has been associated with anti-proliferative and anti-inflammatory effects. 
• This points to a potentially modifiable milieu on the local inflammatory environment and opportunities for anti-stress interventions in endometriosis.

What's done here:

• Following surgically induced endometriosis in female rats, the animals were exposed to either controllable stress (submerged platform) or uncontrollable stress (no platform) or no stress for 10 days.
• At the end of the experiment (day 60), tissue samples were histopathologically and immunohistochemically examined for Vitamin D receptor and macrophage marker (CD68).
• Peritoneal fluids and sera were examined for Vitamin D levels and inflammatory cytokines (IFNɣ, IL-1β, IL-12 p70, IL-10, MCP-1, IL-6, RANTES, and TNFα).
• Human endometriosis tissue microarrays from surgical specimens of endometriosis patients also evaluated for Vitamin D receptor expression.

Key results:

• Serum Vitamin D levels were higher in endometriotic animals compared to the control group, without an important stress effect.
• A stressful environment may increase the development of cysts in endometriosis through local macrophage infiltration, alterations in cytokines, also via an altered Vitamin D: Vitamin D Receptor axis.

Lay Summary

Lopez and colleagues from academic institutions of Puerto Rico published their experimental endometriosis findings on female rats regarding the effect of stress on vitamin D-vitamin D receptor systems and recently published their findings in "Reproductive Sciences". The group previously showed the negative impact of stress in the same animal model of endometriosis. 

Altered levels of vitamin D are noted in patients with endometriosis. Vitamin D signaling through the vitamin D receptor system is known to have anti-proliferative properties. Stress may alter adversely the Vitamin D: Vitamin D Receptor system changing the macrophage behavior and local inflammatory background of endometriosis.

Endometriosis was induced in female rats by surgery and groups of animals were exposed to uncontrollable, controllable, or no stress groups for 10 days.  Vitamin D and cytokine (IFNɣ, IL-1β, IL-12 p70, IL-10, MCP-1, IL-6, RANTES, and TNFα) levels in sera were measured at the end of the experiment on day 60. Vitamin D Receptor expression along with macrophage numbers was investigated. Vitamin D Receptor expression also examined in human samples obtained from surgical pathology archives. 

Serum Vitamin D levels were higher in endometriotic animals compared with the control group, without an important stress effect. Uncontrollable stress increased macrophage infiltration and Vitamin D Receptor expression in vesicles, also attenuated by controllable stress. The number of macrophages correlated with the inflammatory environment with vesicle area, and peritoneal vitamin D levels correlated with vesicle Vitamin D Receptor expression. Decreased expression of some chemokines (chemokine ligand 2 and TGFβ) was observed in the uncontrollable stress group, whereas IL12 increased in the group with controllable stress.

"Stress contributes to the worsening of endometriosis through macrophage recruitment, cytokine changes, and perturbed Vitamin D: Vitamin D Receptor axis, suggesting an impact on the local inflammatory environment. We are still far from a complete understanding of what specific factors may lead to this negative outcome" concluded the researchers.

Research Source: https://pubmed.ncbi.nlm.nih.gov/32583376/