title: Estrogen receptor (ER) agonists differentially regulate neuroangiogenesis in peritoneal endometriosis via the repellent factor SLIT3.
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.
authors: Medical Research Council Centre for Reproductive Health, The University of Edinburgh, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom.
authors: Erin
authors: E
authors: Greaves
authors: Frances
authors: F
authors: Collins
authors: Arantza
authors: A
authors: Esnal-Zufiaurre
authors: Sevasti
authors: S
authors: Giakoumelou
authors: Andrew W
authors: AW
authors: Horne
authors: Philippa T K
authors: PT
authors: Saunders
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004715:Endometriosis / Q000235:genetics / Q000473:pathology; D004717:Endometrium / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology*; D055495:Neurogenesis / Q000187:drug effects* / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology*; D010532:Peritoneal Diseases / Q000235:genetics / Q000473:pathology; D010636:Phenols / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D055815:Young Adult; D011422:Propionates
chemical_list: D004967:Estrogens; D008565:Membrane Proteins; D009570:Nitriles; D010636:Phenols; D011720:Pyrazoles; D011960:Receptors, Estrogen; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C498990:SLIT3 protein, human; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol