The fibronectin receptor α5 integrin subunit is upregulated by cell-cell adhesion via a cyclic AMP-dependent mechanism: Implications for human trophoblast migration

Cell adhesion molecules are implicated in the mechanisms regulating trophoblast migration during human embryo implantation and placentation. We investigated the expression and subcellular organization of the fibronectin receptor α5 integrin subunit during the differentiation of human trophoblasts in vitro, and the role of cyclic adenosine monophosphate (cAMP) in the process. Human trophoblasts isolated from chorionic villi expressed no α5 integrin, but the molecule was upregulated as cells aggregated in vitro. Low levels of expression of α5 integrin subunit and a diffuse cellular distribution pattern were seen in migrating mononuclear trophoblasts. Formation of cell aggregates was accompanied by increased expression of the α5 integrin, which translocated to the cytoskeleton-bound pool of proteins and clustered within focal adhesion plaques on the cell surface. This coincided with increased binding to fibronectin. In the absence of cell-cell adhesion, trophoblasts did not display an increase in α5 integrin messenger RNA or protein and there was no α5 integrin in focal adhesion plaques, suggesting that cell-cell contacts specifically trigger the upregulation of α5 integrin subunit and its subcellular translocation. Cyclic AMP is the second messenger mediating the aggregation-induced increase in α5 integrin: cAMP increased the de novo synthesis of α5 integrin protein, particularly in mononuclear cells, whereas the aggregation-induced increase in α5 integrin was strongly inhibited by the antagonist Rp-cAMP in aggregating cells. Our data provide evidence that the α5 integrin mediates binding of human trophoblasts to fibronectin and is implicated in the regulation of trophoblast migration. This integrin's expression is specifically triggered by cell-cell adhesion and regulated via cAMP-mediated pathway(s). It is hypothesized that these mechanisms may play an important role in the molecular events controlling human placentation.