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Maternal asthma is known to impact intrauterine growth outcomes, which may be mediated, in part, by altered androgen signalling. Our aim was to explore whether the sheep placenta expresses androgen receptor (AR) isoforms and determine if the differential expression of AR protein isoforms is altered by maternal asthma. Four known AR isoforms were detected (AR-FL, AR-v1, AR-v7, and AR-45), and their expression and subcellular distribution was altered in the presence of maternal allergic asthma. These findings underscore the importance for in vivo models of maternal asthma to delineate molecular patterns that may contribute to feto-placental growth and development. [ABSTRACT FROM AUTHOR]

Maternal asthma increases the risk of adverse pregnancy outcomes and may affect fetal growth and placental function by differential effects on the expression of glucocorticoid receptor (GR) isoforms, leading to altered glucocorticoid signalling. Our aim was to examine the effect of maternal asthma on placental GR profiles using a pregnant sheep model of asthma. Nine known GR isoforms were detected. There was a significant increase in the expression of placental GR isoforms that are known to have low trans-activational activity in other species including GR A, GR P and GRγ which may result in a pro-inflammatory environment in the presence of allergic asthma. [ABSTRACT FROM AUTHOR]

Abstract: Workshops are an important part of the IFPA annual meeting. At the IFPA meeting 2008 diverse topics were discussed in 12 themed workshops. Topics covered included: immunology of placentation; galectins and trophoblast invasion; signaling in implantation and invasion; markers to identify trophoblast subpopulations; placental pathology; placental toxicology; stereology; placental transport of fatty acids; placental mesenchymal stem cells; comparative placentation; trophoblast and neoplasia; trophoblast differentiation. This report is a summary of the various topics covered. [Copyright &y& Elsevier]

Matrix metalloproteinases (MMPs) are the main mediators of extracellular matrix degradation. This confers an important role to these enzymes in the invasion of the trophoblast cells where their expression are spatiotemporally regulated. The regulation of MMPs activity is complex and is established at different levels. Their expressions depend on various cis-elements in their gene promoter, and are induced or repressed by various soluble factors. After expression and secretion, the proMMPs must be activated through an activation network. Then, the enzyme activity is regulated by inhibition or stabilization. In this review, we shall focus on the expression, the role in invasion and the regulation of MMPs in the human placenta. [Copyright &y& Elsevier]

Cytotrophoblastic cells (CTBs) from first trimester placenta follow one of two existing differentiation pathways: villous CTBs (vCTBs) form a monolayer of polarized epithelial stem cells which proliferate and eventually differentiate by fusion to form a syncytiotrophoblast (STB) covering the entire surface of the villus, or they can break through the STB at selected sites (in anchoring villi) to form multilayered columns of non-polarized but invasive CTBs. In vitro, CTBs invade a reconstituted basement membrane, they thus behave like metastatic cells. This invasive behaviour is due to the ability of CTBs to secrete matrix metalloproteinases (MMPs) since tissue inhibitor of MMP (TIMP) inhibits their invasiveness. MMPs are a family of at least 17 human zinc-dependent endopeptidases collectively capable of degrading essentially all components of the extracellular matrix (ECM). Although CTBs behave like metastatic cells, in vivo they are only transiently invasive (first trimester) and their invasion is normally limited only to the endometrium and to the proximal third of the myometrium. This temporal and spatial regulation of trophoblast invasion is believed to be mediated in an autocrine way by trophoblastic factors and in a paracrine way by uterine factors. Several types of regulators have been investigated: hormones, cytokines, growth factors and ECM glycoproteins. This review is not intended to be an exhaustive catalogue of all the potential regulators but is aimed at emphasizing those factors relevant in trophoblast-endometrial interactions.

Trophoblast invasion into the uterine wall is controlled by many factors. Previously, a human chorionic gonadotropin (hCG) receptor has been found to be expressed on invasive trophoblast as well as on choriocarcinoma cells implying a possible role for the hormone in trophoblast invasion. Therefore, this study examined the role of hCG in the invasion of trophoblastic (JEG-3) cells. Increasing hCG concentrations were applied in a trophoblast invasion model, JEG-3, through matrigel-coated filters. The proliferation was quantified by WST-1 cleavage assay. Cell migration was studied by examining the number of cells that had passed the uncoated porous (8-microm pore size) filters. After staining, filters were examined microscopically for cells on the underside of the membrane. A quantitative protease assay was also performed. Flow cytometric analysis of alpha5 and alpha6 integrin subunits, which are essential for interactions between cells and extracellular matrix, was performed. hCG increased significantly (P<0.01) the in vitro invasion of trophoblastic JEG-3 cells in a dose-dependent manner. Migration was also increased by hCG (P<0.01). However, cell proliferation remained unchanged. The second messenger analogue dibutyryl cAMP (db cAMP) and the cAMP elevating factor (forskolin) mimicked the effects of hCG by stimulating a dose-dependent increase of trophoblastic cell UEG-3) invasion. The collagenolytic activity of trophoblastic cells (EG-3) was increased by hCG stimulation. No changes were shown in the expression of alpha5 and alpha6 integrin subunits on JEG-3 cells. In vitro hCG is a regulatory factor of invasion and migration in trophoblastic JEG-3 cells, whereas proliferation is not influenced. The endogenous production of hCG by the trophoblast in vivo implies an autocrine control of invasion processes by hCG.

The regulatory role of in vitro decidualized stromal cells (DESCM) and their main secretory product insulin-like growth factor binding protein-1 (IGFBP-1) was studied on the secretion of trophoblastic gelatinases and tissue inhibitor of metalloproteinase (TIMP-1). First trimester cytotrophoblastic cells (CTB) were obtained from abortions and cultured in vitro in presence or absence of DESCM or IGFBP-1. Secreted gelatinases were analysed in the culture supernatants by zymography and by measurements of the total gelatinolytic activity. TIMP-1, hCG, and fetal fibronectin (fFN) were measured by commercially available immunoassays. DESCM inhibited the total gelatinolytic activity of CTB but increased trophoblastic MMP-9, TIMP-1 and fFN. In contrast, IGFBP-1 increased the total gelatinolytic activity and TIMP-1, had no effect on MMP-2 , MMP-9 or fFN but inhibited hCG. It is concluded that a factor secreted by decidual cells inhibits the gelatinolytic property of trophoblast by increasing TIMP-1. Other decidual factors, as yet unidentified, increase MMP-2 and MMP-9 to an extent which does override the inhibitory effect of TIMP-1. Since in contrast to DESCM, IGFBP-1 increases the total gelatinolytic activity of CTB, it cannot be the primary active decidual factor regulating the proteolytic activity of CTB. The possibility of an integrin-mediated effect of IGFBP-1 on CTB is discussed.

In an immunoperoxidase study, pregnancy-associated placental protein A (PAPP-A) was localized to the cytoplasm of decidual stromal cells, the villous syncytiotrophoblast and on the surface of placental trophoblast. A decidual and a trophoblastic origin is suggested for PAPP-A, and its presence on the surface of the syncytiotrophoblast is interpreted as a possible immunoprotective layer.

Pregnancy-associated plasma protein A (PAPP-A), a macromolecular glycoprotein associated with pregnancy, was shown to inhibit complement-induced haemolysis and to bind heparin reversibly. Because of the inhibitory effects of heparin on the complement cascade it was not clear if the inhibition of complement activity observed with PAPP-A (isolated from heparin plasma) was attributable to the heparin moiety bound to PAPP-A. This work demonstrates that heparin exerts an inhibitory effect on complement activity but that heparin-free PAPP-A is also inhibitory. PAPP-A specifically inhibits C3 by binding to this complement subcomponent and not by inhibiting C3 convertase as demonstrated for C3 inactivator.

Pregnancy-associated plasma protein-A (PAPP-A) was purified to homogenicity from third-trimester pregnancy plasma using ion exchange chromatography and affinity chromatography on con A-Sepharose and anti-human serum-Sepharose. The elution of PAPP-A, alpha 2-macroglobulin, Cl-inhibitor and alpha 1-antitrypsin was followed by immuno-diffusion. the eluates were tested for stimulation or inhibition of complement-induced haemolysis. PAPP-A markedly inhibits the haemolytic activity of complement.