Abstract
Endometriosis is a prevalent disease defined by the presence of endometrial tissue outside the uterus. Adenosine triphosphate (ATP), as a proinflammatory molecule, promotes and helps maintain the inflammatory state of endometriosis. Moreover, ATP has a direct influence on the two main symptoms of endometriosis: infertility and pain. Purinergic signaling, the group of biological responses to extracellular nucleotides such as ATP and nucleosides such as adenosine, is involved in the biology of reproduction and is impaired in pathologies with an inflammatory component such as endometriosis. We have previously demonstrated that ectonucleotidases, the enzymes regulating extracellular ATP levels, are active in non-pathological endometria, with hormone-dependent changes in expression throughout the cycle. In the present study we have focused on the expression of ectonucleotidases by means of immunohistochemistry and in situ activity in eutopic and ectopic endometrial tissue of women with endometriosis, and we compared the results with endometria of women without the disease. We have demonstrated that the axis CD39-CD73 is altered in endometriosis, with loss of CD39 and CD73 expression in deep infiltrating endometriosis, the most severe, and most recurring, endometriosis subtype. Our results indicate that this altered expression of ectonucleotidases in endometriosis boosts ATP accumulation in the tissue microenvironment. An important finding is the identification of the nucleotide pyrophophatase/phosphodiesterase 3 (NPP3) as a new histopathological marker of the disease since we have demonstrated its expression in the stroma only in endometriosis, in both eutopic and ectopic tissue. Therefore, targeting the proteins directly involved in ATP breakdown could be an appropriate approach to consider in the treatment of endometriosis.
Highlights
Endometriosis is a chronic gynecological estrogen-dependent disease characterized by the presence of endometrial tissue, both glands and stroma, outside the uterus
Protein expression of NTPDase1 (CD39 from here on), NTPDase2, NTPDase3, nucleotide pyrophophatase/phosphodiesterase 3 (NPP3), 5 -nucleotidase (5 -NT) (CD73 from here on), and CD26 was detected in the eutopic and ectopic endometrial tissue of women with endometriosis
We examined the presence of ectonucleotidases in eutopic and ectopic endometrial tissue in endometriosis
Summary
Endometriosis is a chronic gynecological estrogen-dependent disease characterized by the presence of endometrial tissue, both glands and stroma, outside the uterus. There are multiple possible locations for this ectopic tissue which may be grouped into three endometriosis subtypes: peritoneal, ovarian, with ovarian cysts called endometriomas, and deeply infiltrative. It is a debilitating disorder affecting around 10% of women of reproductive age [1], with pelvic pain and infertility as the two main symptoms. Purinergic signaling is studied in the context of human reproduction [7,8,9,10,11]; for instance, ATP is involved in the initiation and maintenance of myometrium and oviduct contractions. Extracellular ATP and its derivative adenosine influence cell migration, proliferation and survival—three necessary events for the establishment of ectopic endometrial foci
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