Endometriosis is common estrogen dependent gynaecological disease that impacts 1 in 9 women and girls of reproductive age. The most prominent symptom of endometriosis is chronic pelvic pain. Palmitoylethanolamide (PEA) is an endocannabinoid that modulates nociceptive pain perception via the cannabinoid receptors CNR1, CNR2 and the TRVP1 receptor. PEA is degraded by the enzyme FAAH. Recently, we identified VEZT as an endometriosis risk associated gene and when overexpressed in endometrial stromal cells, VEZT upregulated the expression of FAAH.
The aim of this study was to investigate the regulatory role VEZT had on the PEA pathway, receptors, enzymes and determine a mechanism of action.
Methods: PEA pathway gene expression were performed by qPCR under vehicle, estradiol and PEA treatment conditions. Proliferation assays were used to assess PEA effects on cell growth and Immunohistochemistry (IHC) was used to identify protein expression in endometrial tissue and endometriotic lesions.
Results: Under estrogenic conditions, stromal cell expression of TRVP1 was unchanged, while PEA synthesis enzymes (DAGL, NAPE/PLD) were downregulated as well as the PEA receptors (PPARA, CNR1, CNR2). These findings indicated the estrogenic environment of endometriosis interferes with the nociceptive functionality of the PEA pathway. Further, estradiol upregulated VEZT, FAAH and TGFB (a cytokine upregulated in endometriosis). While silencing VEZT and TGFB down regulated FAAH expression, estradiol reversed these effects indicating the upregulation of the PEA degradation enzyme FAAH under endometriosis conditions, is under the control of estrogen. PEA treatment of stromal cells reduced FAAH expression and slowed cell growth in a dose dependent manner but again estradiol reversed these effects. FAAH protein was diffusely localised in basalis stromal cells and was strongly associated with more severe forms of endometriotic lesions.
Conclusions: The PEA pathway is disrupted in severe forms of endometriosis due to the highly estrogenic environment upregulation of the PEA degradation enzyme FAAH.