S. Mizutani demonstrated investigations on placental aminopeptidases in relation to bioactive peptides such as oxytocin, vasopressin and angiotensin, which are highly uterotonic and vasoactive and possibly derived from the fetus. Their studies were initially designed to clarify both the mechanism involved in the onset of labor and the etiology of preeclampsia (PE).
Primarily, oxytocinase and angiotensinase in the placenta were determined to be P-LAP and aminopeptidase A (APA), respectively. P-LAP hydrolyzes oxytocin, vasopressin and angiotensin III, and APA hydrolyzes angiotensin II, all quite actively [7
]. It was also shown that changes in maternal serum P-LAP and APA are useful for predicting both the onset of labor and preterm labor as well as pre-eclampsia, respectively. Cloning P-LAP from a human placental cDNA library showed that the enzyme is a type II integral membrane protein, similar to APA. AP-2 and ikaros were found to cooperatively enhance P-LAP transcription in trophoblastic cells. In addition, forskolin (FSK) treatment was shown to upregulate P-LAP gene expression via AP-2, putatively AP-2α, which is upregulated with trophoblast differentiation [8
]. Animal studies with APA on not only APA deficient mouse but also spontaneously hypertensive rat and Dahl salt-sensitive rat suggested a pivotal role of APA via degradation of A-II in hypertension [9
The results of these basic and applied investigations suggested that the imbalance between the concentration of fetal bioactive peptides and placental aminopeptidase activities might result in the predominance of bioactive peptides in the feto-placental unit and their subsequent leakage into the maternal site occurs with the onset of labor, preterm labor, and pre-eclampsia.