Estrogen Receptor (ER) Agonists Differentially Regulate Neuroangiogenesis in Peritoneal Endometriosis via the Repellent Factor SLIT3

Erin Greaves, Frances Collins, Arantza Esnal-Zufiaurre, Arantza Esnal‐Zufiaurre, Sevasti Giakoumelou, Andrew W Horne, Philippa T K Saunders
Endocrinology · 2014 · vol. 155(10) , pp. 4015–4026 · doi:10.1210/en.2014-1086 · PMID:25051436 · W2043373191
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Estrogen receptor agonists differentially regulate neuroangiogenesis in endometriosis lesions via SLIT3, which is upregulated by ERβ agonists and promotes angiogenesis while inhibiting neurogenesis.

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Abstract

Endometriosis is an estrogen-dependent neurovascular disorder characterized by growth of endometrial tissue (lesions) outside the uterine cavity. Patients suffer chronic pelvic pain, and it has been proposed that co-recruitment of nerves/blood vessels (neuroangiogenesis) into the lesions is fundamental to the development of painful symptoms. We hypothesized that estrogen-dependent regulation of axonal guidance molecules of the SLIT/ROBO (Roundabout) family could play a role in neuroangiogenesis occurring in endometriosis lesions found on the peritoneal wall. In tissue samples from human patients and a mouse model of endometriosis, concentrations of mRNA encoded by SLIT3 were significantly higher in lesions than normal peritoneum. Estrogen regulation of SLIT3 was investigated using 17β-estradiol and selective agonists for each subtype of estrogen receptor (ER) (ERα agonist, 4,4',4″-(4-propyl-(1H)-pyrazole-1,3,5-tryl) trisphenol; ERβ agonist, 2,3-bis(4-hydroxy-phenyl)-propionitrile [DPN]). In mice, DPN (EC50 0.85) increased Slit3 mRNA concentrations compared with hormone-depleted and 17β-estradiol-treated (EC50 0.1) animals and decreased the density of nerves but not vessels in endometriosis lesions. SLIT3 mRNA concentrations were increased in DPN-treated human endometrial endothelial cells and in 4,4',4″-(4-propyl-(1H)-pyrazole-1,3,5-tryl) trisphenol-treated (EC50 200) rat dorsal root ganglia neurons. Functional assays (neurite outgrowth, network formation) revealed that SLIT3 promotes angiogenesis but decreases neurogenesis. In conclusion, these data suggest that estrogen-dependent expression of SLIT3 may play a key role in regulating nerve-vessel interactions within the complex microenvironment of endometriosis lesions.

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Condition tags

mesh:D004715endometriosischronic_pelvic_pain

MeSH descriptors

Estrogens Membrane Proteins Neovascularization, Pathologic Neurogenesis Nitriles Phenols Pyrazoles Receptors, Estrogen Adolescent Adult Animals Cells, Cultured Embryo, Mammalian Endometriosis Endometriosis Endometriosis Endometrium Endometrium Endometrium Endometrium

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