The pappalysins and their substrates in early pregnancy

Abnormal levels of pregnancy-associated plasma proteins -A and -A2 (PAPP-A and PAPP-A2) have been associated with adverse pregnancy outcomes, including preeclampsia and intrauterine-growth-restriction, two leading causes of maternal and perinatal mortality. The goal of this thesis was to assess the roles of PAPP-A, PAPP-A2, and their substrates, insulin-like growth factor-binding proteins -4 and -5 (IGFBP-4 and IGFBP-5), in early pregnancy. In contrast to previous findings with PAPP-A, first trimester maternal serum levels of PAPP-A2 were elevated in pregnancies that subsequently developed preeclampsia. In a model of early placental development, IGFBP-4 and IGFBP-5 inhibited the migration-stimulating effects of insulin-like growth factors -I and -II, although to different extents. Investigation of the location of IGFBP-4 and IGFBP-5 in the placenta revealed sites of protein localization that suggest previously unknown functions. Taken together, these findings suggest different roles of PAPP-A and PAPP-A2 in the first trimester placenta.