Mouse Model For Amniotic Fluid Volume Regulation

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DESCRIPTION (provided by applicant): A comprehensive understanding of the control of amniotic fluid volume is of major clinical importance. We have previously identified a vascular pathway within the fetal membranes for the transfer of fluid from the amniotic compartment into the fetal blood. This pathway is constituted by a network of microvessels on the surface of the placenta and, in sheep, within the amnion and chorion as well. We hypothesize that vascular endothelial growth factor (VEGF) is the determining factor for the absorptive capacity of this intramembranous pathway, thus an important regulator of amniotic fluid volume. In the present application, we propose to develop a mouse model of polyhydramnios and oligohydramnios. The model will be generated using targeted suppression or induction of VEGF gene expression in the fetal membranes and placenta. The advantage of the mouse model is that, it allows the study of the role of VEGF in intramembranous absorption by genetic manipulation. Three specific aims are proposed. Specific Aim 1 proposes to produce polyhydramnios by suppression of VEGF gene expression using a VEGE antisense sequence and oligohydramnios by over-expression of VEGF in the fetal membranes and placenta. Abnormalities in fetal lung development due to amniotic fluid volume changes will be studied. Specific Aim 2 will investigate the proliferation of microvessels in the amnion, chorion and placenta of pregnant mice with polyhydramnios or oligohydramnios. The change in amniotic fluid volume in relation to intramembranous microvessel density and VEGF gene expression will be correlated. Specific Aim 3 will examine fetal and postnatal growth patterns in the polyhydramniotic or oligohydramniotic models, and explore the development of blood pressure disorders in adulthood. The overall hypothesis is that in the pregnant mouse, alterations in amniotic fluid volume can be induced by genetic manipulation of the VEGF gene thus generating models for polyhydramnios and oligohydramnios. The proposed study is an innovative approach to understanding amniotic fluid volume regulation. The models of polyhydramnios and oligohydramnios allow investigation of fetal and postnatal growth and developmental defects due to abnormal amniotic fluid volume in utero. Results from these studies will be important for diagnosis and treatment of amniotic fluid volume disorders during pregnancy.