Activin A regulates trophoblast cell adhesive properties: implications for implantation failure in women with endometriosis-associated infertility.
BACKGROUND
During implantation, the embryo adheres to the endometrium via cell adhesion molecules (CAMs) present on blastocyst trophectoderm and endometrial epithelial cells. CAMs, including integrins and extracellular matrix (ECM) ligands, are most likely regulated by hormones, cytokines and growth factors. We hypothesized first that activin A affects the adhesive properties of trophoblast cells and second that alterations in dimeric activin A levels in the uterine cavity could disrupt adhesion, thereby causing implantation failure.


METHODS
This study examined effects of activin A on trophoblast cell adhesion and measured activin A levels in secretory phase uterine washings from women with and without endometriosis (EOS). Activin receptor expression on trophoblast (HTR8) cells was examined by RT-PCR, and adhesive molecules measured by integrin antibody and cell-matrix adhesion assays. Dimeric activin A was measured (enzyme-linked immunosorbent assay) in uterine washings (14 controls and 23 EOS), and betaA-subunit localization was verified in endometrial tissues.


RESULTS
Activin receptors are expressed by HTR8 cells. Activin A activated Smad2 in a concentration-dependent manner which was blocked by an activin receptor inhibitor (SB431542). Following activin A treatment (50 ng/ml for 24 h), trophoblast cell surface integrins alpha1 alpha2 alpha3 alpha5, beta1, beta2, beta4 and alphavbeta5 were decreased, as was cell binding to the ECM ligands, fibronectin, collagen IV and collagen I (P < 0.05). Activin A was detected in 56.5% of EOS and 21.4% of control washings, with measured levels from 42 to 8481 pg/ml (not significantly different).


CONCLUSIONS
Decreased trophoblast CAM production and adhesion could be caused by dysregulated local activin A levels and may contribute to implantation failure. This could explain, in part, the infertility observed in women with EOS.
Stoikos
Chelsea J
CJ
Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3800, Australia.
Salamonsen
Lois A
LA
Hannan
Natalie J
NJ
O'Connor
Anne E
AE
Rombauts
Luk
L
Dimitriadis
Evdokia
E
D029404:Activin Receptors / Q000378:metabolism; D028341:Activins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D010064:Embryo Implantation / Q000502:physiology*; D004715:Endometriosis / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007247:Infertility, Female / Q000209:etiology* / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019096:Vitronectin / Q000378:metabolism
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D005353:Fibronectins; D016023:Integrins; D007797:Laminin; D021122:Protein Subunits; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D019096:Vitronectin; C422405:activin A; D028341:Activins; D003094:Collagen; D029404:Activin Receptors