Expression of urokinase, plasminogen activator inhibitors and urokinase receptor in pregnant rhesus monkey uterus during early placentation.

We have investigated plasmin mediated proteolysis associated with trophoblast invasion during early stages of pregnancy in the rhesus monkey. In situ hybridization and immunocytochemical localization were used to define the cellular and tissue distribution of urokinase plasminogen activator (uPA), plasminogen activator inhibitor type 1 (PAI-1) and 2 (PAI-2) and urokinase receptor in early monkey placenta and uterus. Our results indicate: (1) uPA is expressed in proliferating and invasive cytotrophoblast located in chorionic villi as well as in extravillous trophoblast associated with uterine arterioles. This raises the possibility that urokinase may play an important role in trophoblast invasion. (2) PAI-1 mRNA is specifically localized in two areas where invasive trophoblast cells encounter maternal tissue directly. The extravillous cytotrophoblast cells at the maternofetal junction express PAI-1 mRNA. The invasive endovascular trophoblast cells within the uterine arterioles also express PAI-1 mRNA. The location sensitive expression of PAI-1 mRNA at the maternofetal junction may imply a protective function of this protease inhibitor that might be induced through interaction with decidual cells. (3) Urokinase receptor antigen has also been found at the maternofetal junction and in endovascular trophoblast cells of the invaded maternal blood vessel. (4) PAI-2 immunoreactivity is found in association with cytotrophoblast cells in anchoring choronic villi suggesting its association with early placentation. In conclusion, we propose that the plasmin/plasminogen activator system may not only regulate extracellular matrix degradation, but also modify migration and invasive behaviour of extravillous trophoblast cells, during early placentation.

Feng Q ，Liu Y ，Liu K ，Byrne S ，Liu G ，Wang X ，Li Z ，Ockleford CD ... -  《PLACENTA》

Plasminogen activators and inhibitors are transcribed during early macaque implantation.

Plasminogen activators and inhibitors may be important early in primate implantation but evidence for this is sparse in non-human primates. We define the expression of urokinase type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1) and type 2 (PAI-2), the receptor for uPA (uPAR) and fibrin/fibrinogen in monkey implantation sites. In situ hybridization and immuno-histochemical localization of rhesus monkey implantation sites (day 15-16 postovulation) indicate: (1) uPA mRNA is localized to placental trophoblast, epithelial plaque and endometrial stroma. (2) tPA mRNA is mainly expressed in glandular cells of endometrium. (3) PAI-1 expression is linked to a specific population of trophoblasts that confront maternal cells, adding support to our view that it has a regulatory role in trophoblast invasion. (4) Localization of tPA antigen confirms that uterine glands are the major source of tPA and that it is also closely associated with fibrin(ogen) suggesting its possible function during implantation is fibrinolysis. (5) Unlike uPA mRNA, however, the distribution of uPA protein and its cell surface receptor uPAR suggests that it mediates trophoblast invasion and plays a significant role in angiogenesis. (6) PAI-2, the inhibitor associated with pregnancy in humans, was found in unidentified cells located specifically along the maternofetal junction. This localization adjacent to areas of cell death at the maternofetal junction implies that it may have a role as a protective curtain with anti-apoptotic function. In conclusion our results suggest that gene expression of PAs and PAIs in early implantation sites are tissue-specific, location-sensitive and function-related.

Feng Q ，Liu K ，Liu YX ，Byrne S ，Ockleford CD ... -  《PLACENTA》

Expression and function of the urokinase type plasminogen activator during mouse hemochorial placental development.

Teesalu T ，Blasi F ，Talarico D 《DEVELOPMENTAL DYNAMICS》

The urokinase-system in tumor tissue stroma of the breast and breast cancer cell invasion.

Hildenbrand R ，Schaaf A 《INTERNATIONAL JOURNAL OF ONCOLOGY》

Expression of tissue type and urokinase type plasminogen activators as well as plasminogen activator inhibitor type-1 and type-2 in human and rhesus monkey placenta.

:The distribution of mRNAs and antigens of tissue type (t) and urokinase type (u) plasminogen activators (PA) plus their corresponding inhibitors, type-1 (PAI-1) and type-2 (PAI-2) were studied in human and rhesus monkey placentae by in situ hybridisation and immunocytochemistry. Specific monkey cRNA and antibodies against human tPA, uPA, PAI-1 and PAI-2 were used as probes. The following results were obtained. (1) All the molecules tPA, uPA, PAI-1 and PAI-2 and their mRNAs were identified in the majority of the extravillous cytotrophoblast cells of the decidual layer between Rohr's and Nitabuch's striae and in cytotrophoblast cells of the chorionic plate, basal plate, intercotyledonary septae and cytotrophoblast cells of the chorionic villous tree. (2) Expression of uPA and PAI-2 was noted in villous trophoblast whereas tPA and PAI-1 were mainly concentrated where detachment from maternal tissue occurs. (3) No expression of tPA, uPA, PAI-1 and PAI-2 was observed in the basal plate endometrial stromal cells, chorionic plate connective tissue cells, septal endometrial stromal cells or villous core mesenchyme. (4) The distribution of probes observed following in situ hybridisation is generally consistent with the immunofluorescence pattern of the corresponding antigens and no significant interspecies differences were noted. It is possible that both decidual and extravillous trophoblast cells of placentae of human and rhesus monkey are capable of producing tPA, uPA, PAI-1 and PAI-2 to differing extents. Coordinated expression of these genes in the tissue may play an essential role in the maintenance of normal placentation and parturition. The differences in distribution we observed are consistent with the suggestion that coordinated expression of tPA and its inhibitor PAI-1 may play a key role in fibrinolytic activity in the early stages of placentation and separation of placenta from maternal tissue at term. On the other hand, uPA with its inhibitor PAI-2 appears mainly to play a role in degradation of trophoblast cell-associated extracellular matrix, and thus may be of greatest importance during early stages of placentation.

Hu ZY ，Liu YX ，Liu K ，Byrne S ，Ny T ，Feng Q ，Ockleford CD ... -  《JOURNAL OF ANATOMY》