MS40. THE FIRST TRIMESTER: CREATING A SUITABLE ENVIRONMENT FOR ORGANOGENESIS. Burton, Graham¹, Jauniaux, Eric², ¹ University of Cambridge, Cambridge, UK² Royal Free and University College, London, UK
     Organogenesis encompasses the period of development from establishment of the primitive streak to closure of the palate. In the human this corresponds to weeks 3-8 post-fertilisation (5-10 weeks menstrual age). It is a period of rapid cell division and differentiation, during which the primordia of the main organ systems are laid down, and hence when the embryo is most vulnerable to perturbations. There is considerable experimental evidence in animal models, and circumstantial evidence in the human, that many teratogens mediate their actions through free radicals, either via their direct effect on DNA to cause mutations or through disruption of signalling pathways. It might be anticipated, therefore, that an important aspect of reproduction is to create a safe and stable environment in which organogenesis can take place. Recent high resolution Doppler imaging, coupled with physiological measurements taken in vivo, has led to a radical reappraisal of the status of the maternal arterial circulation to the placenta during this period. It is now realised that invading endovascular trophoblast cells occlude the tips of the spiral arteries until 10-12 weeks menstrual age, and consequently the oxygen concentration within the feto-placental unit is low (<20 mmHg). Instead, the nutritional demands of the embryo appear to be met in part by secretions from the uterine glands, which remain highly active during early pregnancy and deliver carbohydrate-rich secretions into the placental intervillous space. These nutrients are transported into the exocoelomic cavity, from where they may be taken up by the yolk sac and carried to the embryo. Phylogenetically older metabolic pathways involving non-phosphorylated sugars are highly active in the placental and fetal tissues during this period, and may provide a means of maintaining redox potential under the low oxygen conditions. Once organogenesis is complete at 10 weeks menstrual age the maternal arterial circulation to the placenta starts to be established in a periphery to centre fashion. This is associated with a three-fold increase in intraplacental oxygen concentration, and there is accumulating evidence that failure of the tissues to adapt to this rise lays the foundations of complications of pregnancy such as miscarriage and preeclampsia.

MS41. UTEROPLACENTAL BLOOD FLOW REGULATION AND FETAL GROWTH DURING GESTATION. Magness, Ronald¹, ¹ University of Wisconsin, Madison, WI
     During normal gestation uterine and placental blood flows increase dramatically for adequate fetal growth. Perfusion at the maternal-fetal interface occurs via vasodilatation and angiogenic processes. Understanding these mechanisms is important because IUGR leads to increased fetal morbidity and long-term developmental origins of adult onset diseases (i.e. the Barker Hypothesis). Expression of eNOS, NO production, and cGMP are elevated in the uterine and placental endothelial cells and inhibition of NO production reduces blood flow in both the maternal and fetal compartments. Several important interacting factors are implicated in regulating NO production and reproductive blood flows in normal pregnancy including the observed elevated angiogenic factors, estrogen and fluid shear stress. Placental angiogenic factors and NO together play vital roles in regulating placental angiogenesis while also contributing to vasodilatation. Fetal placental angiogenic activity, bFGF, VEGF secretion, and NO production are increased during the third trimester of pregnancy in parallel with fetal growth and uterine and placental blood flows. Interactions are also observed because bFGF and VEGF have the capability of increasing uterine and placental endothelial NO production via elevations in eNOS activation and/or eNOS expression. Estrogen is a potent uterine vasodilator and its levels are also elevated in normal gestation. Blockade of estrogen receptors (ERs) using ICI 182,780 lowers gravid UBF the same amount as the fall seen with NO inhibition using L-NAME. Estrogen also increases de novo NO production by uterine artery endothelial cells (UAECs) via an ER and ERK-MAPK mediated mechanism. Increases in UBF elevate laminar/pulsatile shear stress and uterine vascular NO production. Unlike static UAEC cultures, in the presence of basal shear stress, E2 dramatically augments the rise in eNOS protein expression. Estrogen and shear stress also elevate angiogenic factor expression and contribute to uterine and placental neovascularization. In conclusion, regulation of coordinated rises in blood flows at the maternal-fetal interface is modulated by convergent NO associated mechanisms that are important to fetal development and long-term health. NIH grants HL49210, HD33255, HL57653, HD38843.

MS42. TESTING THE LIMITS OF MATERNAL-FETAL PARTNERSHIP: ADAPTIVE SUCCESS AND FAILURE UNDER CONDITIONS OF CHRONIC HYPOXIA IN HUMAN PREGNANCY. Zamudio, Stacy¹, Caniggia, Isabella², Illsley, Nicholas³, ¹ New Jersey Medical School, Newark, NJ² Samuel Lunenfeld Research Institute, Toronto, ON, Canada³ New Jersey Medical School, Newark, NJ
     Human pregnancy at high altitude (HA) is a natural experimental model to test the limits of flexibility in placental, maternal and fetal cooperation. HA residence reduces fetal growth (100 grams/1000 m elevation), increases the incidence of preeclampsia 2-4 fold, and, in the absence of high quality medical care, increases maternal, fetal and neonatal mortality. We review here how populations with a long evolutionary history at HA have adapted to the stress of lowered oxygen availability and have ameliorated, but not fully overcome the altitude-associated reduction in fetal growth. This involves fetal, maternal and placental changes related to reduced oxygen availability. At the physiological level, women of HA ancestry have increased blood flow and oxygen delivery to the fetus. Fetuses of HA ancestry have increased oxygen uptake that is proportional to their greater growth, regardless of altitude. Placental structural alterations and maternal and fetal vascular and hematological changes yield greater uteroplacental and fetal blood flows, higher oxygen saturation of the fetal blood and ultimately greater oxygen delivery and uptake in fetuses of HA ancestry. While this contributes to preservation of fetal growth at HA (and larger infants at low altitude), the compensation is not complete, and even the newborns of a genetically adapted population are smaller than their sea level counterparts. At the molecular level there is dissociation of some of the expected effects of hypoxia on placental development and function. Elevated placental hypoxia-inducible factor 1 alpha (HIF-1alpha) message and protein expression are directly correlated with maternal and placental factors relevant to pregnancy outcome at HA, including placental capillary density, maternal circulating VEGF and erythropoietin levels. Elevation in HIF-1alpha in the HA placenta likely contributes to increased placental vascularity, but basal syncytial membrane glucose and amino acid transporter densities are reduced. With respect to glucose this contrasts with in vitro studies and suggests that factors either indirectly related to hypoxia or separate from hypoxia contribute to the reduction in fetal growth at HA, despite preservation of oxygen delivery in the pregnancies of well-adapted populations. Support NSF BCS 0309142, NIH HD 42737.