Retinoic Acid Biosynthesis Is Impaired in Human and Murine Endometriosis1

Keely Pierzchalski, Taylor RN, Robert N. Taylor, Nezhat C, Ceana Nezhat, Jace W. Jones, Napoli JL, Joseph L. Napoli, Guixiang Yang, Yang G, Maureen A. Kane, Kane MA, Neil Sidell, Sidell N
Biology of reproduction · 2014 · vol. 91(4) , pp. 84 · doi:10.1095/biolreprod.114.119677 · PMID:25143356 · PMC4435029 · W2167562037
article OA: bronze CC0 ⤵ 34 in-corpus citations
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Endometriotic lesions exhibit reduced all-trans retinoic acid (ATRA) levels, linked to decreased RBP1 expression, promoting implantation and growth at ectopic sites.

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Abstract

Endometriosis is characterized by the presence of endometrial glands and stroma in extrauterine sites. Our objective was to determine whether endometriotic lesions (ELs) from women with endometriosis have altered retinoid levels compared with their eutopic endometrium, and to test the hypothesis that defects in all-trans retinoic acid (ATRA) biosynthesis in EL is related to reduced expression of cellular retinol-binding protein type 1 (RBP1). Retinoids were evaluated by liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography in eutopic endometrial biopsies (EBs) and ELs from 42 patients with pathologically confirmed endometriosis. The ATRA levels were reduced, whereas the retinol and retinyl ester concentrations were elevated in EL compared with EB tissue. Similar results were found in a mouse model of endometriosis that used green fluorescent protein-positive endometrial tissue injected into the peritoneum of syngeneic hosts to mimic retrograde menses. The ATRA biosynthesis in vitro in retinol-treated primary human endometrial stromal cell (ESC) cultures derived from ELs was reduced compared with that of ESCs derived from patient-matched EBs. Correspondingly, RBP1 expression was reduced in tissue and ESCs derived from EL versus EB. Rbp1(-/-) mice showed reduced endometrial ATRA concentrations compared with wild type, associated with loss of tissue organization and hypercellularity. These findings provide the first quantitative measurements of ATRA in human endometrium and endometriosis, demonstrating reduced ATRA in ectopic tissue and corresponding ESC cultures. Quantitation of retinoids in murine endometriosis and in Rbp1(-/-) mice supports the contention that impaired ATRA synthesis caused by reduced RBP1 promotes an "endometriosis phenotype" that enables cells to implant and grow at ectopic sites.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Retinol-Binding Proteins, Cellular Tretinoin Animals Endometriosis Female Gene Expression Regulation Humans Mice, Knockout Retinol-Binding Proteins, Cellular Retinol-Binding Proteins, Cellular Species Specificity Tretinoin

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