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Differential Roles of Renin and Angiotensinogen in the Feto-Maternal Interface in the Development of Complications of Pregnancy

Tsukuba Advanced Research Alliance (TARA) (E.T.-O., T.S., J.I., A.F.), and Institute of Basic Medical Sciences, Laboratory Animal Resource Center (F.S., K.Y.), University of Tsukuba, Tsukuba, Ibaraki 305-8577; and Division of Biological Sciences (E.T.-O., J.O.), Graduate School of Science, Hokkaido University, Sapporo 060-0810; and Department of Molecular Cell Biology (E.T.-O., J.O.), Medical Research Institute, Tokyo Medical & Dental University, Chiyoda-ku, Tokyo 101-0062, Japan

Address all correspondence and requests for reprints to: Dr. Akiyoshi Fukamizu, Center for Tsukuba Advanced Research Alliance, Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan. E-mail: akif{at}tara.tsukuba.ac.jp.

We previously identified a transgenic mouse model that developed pregnancy-associated hypertension (PAH) and intrauterine growth restriction (IUGR) by mating females expressing human angiotensinogen (hANG) with males expressing human renin (hRN). These phenotypic defects were not observed in the opposite type of mating combination, despite the feto-placental overexpression of hRN and hANG detected in both types of crossbreeding. Detailed analysis of transgene localization in the labyrinth and its permeability to the maternal circulation revealed that hRN produced in trophoblast giant cells was secreted into the maternal circulation, whereas hANG, produced in chorionic trophoblasts and trophoblastic epithelium, was undetectable in the maternal plasma, probably due to their distinct spatial and temporal expression in labyrinth. These results demonstrated that PAH and IUGR could be mediated by feto-placental hRN through its permeability to the maternal circulation, not by feto-placental hANG production. Furthermore, overexpression of maternally derived hANG in decidua and spiral arteries of pregnant females with PAH and IUGR raises the possibility of local activation of the renin-angiotensin system and its pathophysiological effects on placental hypoperfusion in complications of pregnancy. This study provides in vivo evidence that the cell-specific expression of RN and ANG in the feto-maternal interface impacts their differential roles in pregnancy.

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