Review: The ADAM metalloproteinases – Novel regulators of trophoblast invasion?

During pregnancy, the extravillous trophoblast (EVT) invades the maternal decidua and remodels spiral arteries reaching as far as the inner third of the myometrium. This process is mandatory to a successful pregnancy since EVTs regulate spiral artery remodeling to achieve maximal vasodilation and thus an adequate nutrient supply to the embryo or communicate with maternal leukocyte populations to guarantee acceptance of the allogeneic conceptus. To achieve this, EVTs undergo a remarkable and unique differentiation process, which yields different phenotypes such as proliferative cell column trophoblasts or growth-arrested, invasive interstitial or endovascular cytotrophoblasts. Matrix metalloproteinases have long been seen as imperative to trophoblast invasion because of their ability to degrade extracellular matrix and therefore allow cellular movement in foreign tissues. However, global gene expression analysis reveals that EVTs also express various members of distintegrin and metalloproteinases (ADAMs). These proteases are associated with the process of proteolytic shedding and activation of surface proteins including growth factors, cytokines, receptors and their ligands rather than extracellular matrix breakdown. While ADAM12 has been associated with chromosomal abnormalities as well as preeclampsia or intrauterine fetal growth restriction, the function of ADAMs in trophoblasts remains elusive. In this article, we review the diverse invasive trophoblast phenotypes, EVT-associated protease systems and related open questions. In addition, we examine recent information about relevant ADAM members and their putative implications for EVT biology.