Recent studies have shown that amniotic fluid (AF) volume is regulated by modulating the rate of intramembranous absorption and that vascular endothelial growth factor (VEGF) may play a pivotal role in this regulation. This absorption occurs against hydrostatic, concentration and experimentally induced osmotic gradients. However, the mechanisms mediating intramembranous transport as well as the regulation of intramembmnous absorption are unknown. The proposed studies utilize chronically catheterized fetal sheep to characterize intramembranous transport mechanisms and determine the underlying cellular and molecular regulation during normoxia and during 3 forms of fetal hypoxia which individually produce increased, unchanged, or reduced AF volume. We will determine the contribution of diffusion versus bulk transport to intramembranous absorption of water and solutes. These interpretations will be confirmed by measuring the intramembranous unidirectional fluxes of specific solutes in the AF to fetal and fetal to AF directions. The cellular and molecular mechanisms which regulate passive and bulk transfer through the intramembranous pathway will be determined by studying the effects of VEGF on transport in isolated amniotic membrane and amnion cells in culture. Our overall hypothesis is that intramembranous bulk flow occurs by unidirectional vesicular transport; that hypoxia augments bulk flow but not passive diffusion; and that the rate of vesicular transport is determined by the abundance and mobility of vesicles in the amnion. We further hypothesize that hypoxia augments VEGF expression which in turn regulates caveolin-1 expression and/or increases vesicle abundance and mobility. The proposed studies are important because oligohydramnios is a frequent clinical problem associated with fetal hypoxia accounting for many in utero fetal deaths due to cord compression and neonatal deaths due to respiratory distress. Polyhydramnios is associated with premature delivery and fetal diseases including anemic hypoxia. The proposed studies will lead to a dramatic improvement in our understanding of AF volume regulation under normal as well as hypoxic conditions. This knowledge will promote a rational basis for improved therapies to treat AF volume abnormalities, thereby helping to reduce fetal and neonatal morbidity and mortality.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Ilekis, John V
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Oregon Health and Science University
Obstetrics & Gynecology
Schools of Medicine
United States
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Brace, Robert A; Cheung, Cecilia Y (2011) Amniotic fluid volume and composition after fetal membrane resection in late-gestation sheep. J Am Assoc Lab Anim Sci 50:939-42
Faber, J Job; Anderson, Debra F (2010) The placenta in the integrated physiology of fetal volume control. Int J Dev Biol 54:391-6
Cheung, Cecilia Y; Li, Sumin; Chen, Dongbao et al. (2010) Regulation of caveolin-1 expression and phosphorylation by VEGF in ovine amnion cells. Reprod Sci 17:1112-9
Faber, J J; Brace, R A; Davis, L E et al. (2009) Ovine amniotic fluid volume response to intra-amniotic balloon filling. Placenta 30:201-2
Jellyman, Juanita K; Cheung, Cecilia Y; Brace, Robert A (2009) Amniotic fluid volume responses to esophageal ligation in fetal sheep: contribution of lung liquid. Am J Obstet Gynecol 200:313.e1-6
Gesteland, Katherine M; Anderson, Debra F; Davis, Lowell E et al. (2009) Intramembranous solute and water fluxes during high intramembranous absorption rates in fetal sheep with and without lung liquid diversion. Am J Obstet Gynecol 201:85.e1-6
Robertson, Patricia; Faber, J Job; Brace, Robert A et al. (2009) Responses of amniotic fluid volume and its four major flows to lung liquid diversion and amniotic infusion in the ovine fetus. Reprod Sci 16:88-93
Cheung, Cecilia Y; Brace, Robert A (2008) Unidirectional transport across cultured ovine amniotic epithelial cell monolayer. Reprod Sci 15:1054-8
Cheung, Cecilia Y; Brace, Robert A (2008) Hypoxia modulation of caveolin-1 and vascular endothelial growth factor in ovine fetal membranes. Reprod Sci 15:469-76
Brace, Robert A; Cheung, Cecilia Y; Davis, Lowell E et al. (2006) Sources of amniotic fluid erythropoietin during normoxia and hypoxia in fetal sheep. Am J Obstet Gynecol 195:246-54

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