Submission Number: RUS-4-404-176

Abstract Number: 3

PLACENTAL INSUFFICIENCY-INTRAUTERINE GROWTH RESTRICTION IN SHEEP.

Russell V Anthony* ^1,2, Timothy RH Regnault ², RJ Orbus ¹, B deVrijer ², Sean W Limesand ¹, HL Galan ² and Randall B Wilkening ²

Colorado State University, Fort Collins, CO ¹
University of Colorado Health Sciences Center, Denver, CO ²

Abstract:
Intrauterine growth restriction (IUGR) is a significant cause of increased infant mortality and morbidity. Furthermore, there is now compelling evidence that IUGR contributes to a predisposition for coronary heart disease, hypertension, stroke and diabetes during adulthood. The majority of IUGR fetuses exhibit asymmetric patterns of growth, and are associated with placental insufficiency (PI). A variety of animal models of IUGR have been developed, but those in sheep provide the opportunity to evaluate placental nutrient transfer as well as fetal development and physiology. We have used the natural phenomenon of hyperthermia-induced PI-IUGR in sheep to examine placental development, function and placental-fetal interactions. The PI-IUGR that results from exposure to elevated ambient temperatures, during the period of maximal placental growth, manifests an 50% reduction in both placental and fetal size near term. Furthermore, this model of PI-IUGR exhibits many of the hallmarks observed in human IUGR pregnancies, such as asymmetric fetal growth, fetal hypoxia and hypoglycemia, increased umbilical artery pulsatility index, and impaired placental nutrient transport. Presently, our studies of PI-IUGR have focused on placental endocrinology and angiogenesis, during the period of maximal placental development (40 to 90 days post coitus; dpc). Maternal concentrations of progesterone and placental lactogen (PL) are significantly lower before significant differences in placental weight are observed, though concentrations of PL mRNA and protein in the placenta are not altered. Additionally, changes in expression of mRNA encoding steroidogenic acute regulatory protein, cytochrome P450 side chain cleavage enzyme and 3-hydroxysteroid dehydrogenase do not fit with reduced steroidogenic capacity of these placenta. These results may indicate that in addition to later reductions in placental mass, a failure of chorionic binucleate cells to migrate, fuse and deliver their products (PL and progesterone) to maternal syncytium may explain the reduction of placental hormone concentrations. Moreover, utero-placental growth hormone (GH) expression is virtually abolished at 55 dpc in PI-IUGR tissues. The lack of utero-placental GH expression, and potential alterations of insulin-like growth factor (IGF) or IGF-binding protein production, may play a role in the depressed growth and development of the PI-IUGR placenta. Also, expression of vascular endothelial growth factor (VEGF) mRNA is elevated, placental growth factor (PlGF) expression is unaltered, and endothelial nitric oxide synthase (eNOS) production is reduced at 55 dpc. These changes occur prior to observed placental vascular alterations at 90 dpc, which coincides with the end of placental growth in sheep. The alterations in VEGF and eNOS expression could help explain observed differences in placental vascular structure and vascular resistance, respectively. While having just scratched the surface, we are beginning to better understand why placental vasculature and hormone production are altered in PI-IUGR pregnancies, which should eventually lead to an understanding of why the PI-IUGR placenta fails to meet the requirements of the developing fetus.

Keywords: placental insufficiency, intrauterine growth restriction, placental angiogenesis, placental hormones

This abstract is being presented at: 11:30 AM in session:
Minisymposium IV: FETAL ORIGINS OF ADULT DISEASES