Browsing by Autor "Zamudio, Stacy"

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Evidence for extraplacental sources of circulating angiogenic growth effectors in human pregnancy
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2013) Zamudio, Stacy
Abastract. Pregnancy complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR) are associated with reduced blood flow, contributing to placental and fetal hypoxia. Placental hypoxia is thought to cause altered production of angiogenic growth effectors (AGEs), reflected in the circulation of mother and fetus. Vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and their soluble binding protein (sFlt-1) are, in turn, postulated as being causally involved in PE via induction of systemic endothelial cell dysfunction. To dissect the role of AGEs, accurate measurement is of great importance. However, the values of AGEs are highly variable, contributing to heterogeneity in their association (or lack thereof) with preeclampsia. To test the hypothesis that variability may be due to peripheral cell release of AGEs we obtained blood samples from normal healthy pregnant women (n ¼ 90) and the cord blood of a subset of their neonates using standard serum separation and compared results obtained in parallel samples collected into reagents designed to inhibit peripheral cell activation (sodium citrate, theophylline, adenosine and dipyridamole-CTAD). AGEs were measured by ELISA. CTAD collection reduced maternal and fetal free VEGF by 83%, and 98%, respectively. Free PlGF was decreased by 29%, maternal sFlt-1 by >20% and fetal sFlt-1 by 59% in the CTAD-treated vs. serum sample (p < 0.0001). In summary blood collection techniques can profoundly alter measured concentrations of AGEs in mother and fetus. This process is highly variable, contributes to variation reported in the literature, and renders questionable the true impact of alteration in AGEs on pregnancy pathologies.
Hypoglycemia and the origin of hypoxia-induced reduction in human fetal growth
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2010) Zamudio, Stacy
Abtract. Background: The most well known reproductive consequence of residence at high altitude (HA .2700 m) is reduction in fetal growth. Reduced fetoplacental oxygenation is an underlying cause of pregnancy pathologies, including intrauterine growth restriction and preeclampsia, which are more common at HA. Therefore, altitude is a natural experimental model to study the etiology of pregnancy pathophysiologies. We have shown that the proximate cause of decreased fetal growth is not reduced oxygen availability, delivery, or consumption. We therefore asked whether glucose, the primary substrate for fetal growth, might be decreased and/or whether altered fetoplacental glucose metabolism might account for reduced fetal growth at HA. Methods: Doppler and ultrasound were used to measure maternal uterine and fetal umbilical blood flows in 69 and 58 residents of 400 vs 3600 m. Arterial and venous blood samples from mother and fetus were collected at elective cesarean delivery and analyzed for glucose, lactate and insulin. Maternal delivery and fetal uptakes for oxygen and glucose were calculated. Principal Findings: The maternal arterial – venous glucose concentration difference was greater at HA. However, umbilical venous and arterial glucose concentrations were markedly decreased, resulting in lower glucose delivery at 3600 m. Fetal glucose consumption was reduced by .28%, but strongly correlated with glucose delivery, highlighting the relevance of glucose concentration to fetal uptake. At altitude, fetal lactate levels were increased, insulin concentrations decreased, and the expression of GLUT1 glucose transporter protein in the placental basal membrane was reduced. Conclusion/Significance: Our results support that preferential anaerobic consumption of glucose by the placenta at high altitude spares oxygen for fetal use, but limits glucose availability for fetal growth. Thus reduced fetal growth at high altitude is associated with fetal hypoglycemia, hypoinsulinemia and a trend towards lactacidemia. Our data support that placentally-mediated reduction in glucose transport is an initiating factor for reduced fetal growth under conditions of chronic hypoxemia.
Maternal and fetoplacental hypoxia do not alter circulating angiogenec growth effectors during human pregnancy
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2014) Zamudio, Stacy
Abstract. One causal model of preeclampsia (PE) postulates that placental hypoxia alters the production of angiogenic growth effectors (AGEs), causing an imbalance leading to maternal endothelial cell dysfunction. We tested this model using the natural experiment of high-altitude (HA) residence. We hypothesized that in HA pregnancies 1) circulating soluble fms-like tyrosine kinase 1 (sFlt-1) is increased and placental growth factor (PlGF) decreased, and 2) AGE concentrations correlate with measures of hypoxia. A cross-sectional study of healthy pregnancies at low altitude (LA) (400 m) versus HA (3600 m) compared normal (n ¼ 80 at HA, n ¼ 90 at LA) and PE pregnancies (n ¼ 20 PE at HA, n ¼ 19 PE at LA). Blood was collected using standard serum separation and, in parallel, by a method designed to inhibit platelet activation. AGEs were measured by enzyme-linked immunosorbent assays. AGEs did not differ between altitudes in normal or PE pregnancies. AGE concentrations were unrelated to measures of maternal or fetal hypoxia. PlGF was lower and sFlt-1 higher in PE, but overlapped considerably with the range observed in normal samples. PlGF correlated with placental mass in both normal and PE pregnancies. The contribution of peripheral cells to the values measured for AGEs was similar at LA and HA, but was greater in PE than in normotensive women. Hypoxia, across a wide physiological range in pregnancy, does not alter levels of circulating AGEs in otherwise normal pregnancies. Peripheral cell release of AGEs with the hemostasis characteristic of standard blood collection is highly variable and contributes to a doubling of the amount of sFlt-1 measured in PE as compared to normal pregnancies.
Maternal and fetoplacental hypoxia do not alter circulating angiogenic growth factors : the emperor's got no clothes?
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2010) Zamudio, Stacy
ABSTRACT. Context: Placental hypoxia alters production of angiogenic growth factors (AGFs), thought to be causally involved in the development of the pregnancy-specific disease preeclampsia (PE). Consistent with this, the incidence of PE is increased at high altitude (HA, >2700m). Objective. We tested the hypotheses that (1) circulating sFlt-1 is increased and free VEGF and PlGF decreased at HA, (2) circulating AGFs correlate with biomarkers of hypoxia, (3) peripheral circulating cells may contribute to hypoxia-associated alterations in AGFs, and (4) cord blood levels of AGFs are altered at HA or in PE. Design. A prospective, cross-sectional study of healthy and preeclamptic pregnancies at low (400m) vs. HA (3600m) in Bolivia. Participants. Subjects (170 normal, 39 PE) conceived, gestated and delivered at their altitude of residence. Healthy women had no conditions predisposing to preeclampsia. Methods: Blood was collected using standard techniques and those designed to inhibit platelet activation. Maternal and fetal AGFs were measured by ELISA and compared between altitudes, between normal and PE pregnancies and in relation to biomarkers of hypoxia. Results: AGFs did not differ between altitudes. >90% of circulating free VEGF, >30% of PlGF and >25% of sFlt-1 was secreted into samples as a consequence of hemostasis. Biomarkers of hypoxia did not correlate with the AGFs. PlGF was lower and sFlt-1 higher in PE. PlGF correlated with placental mass, whilst significantly more sFlt-1 derived from circulating peripheral cells in PE than normotensive patients. Conclusions. Chronic hypoxia does not alter circulating AGFs. Smaller placentas likely account for diminished PlGF in PE. Peripheral cell release of AGFs provoked by hemostasis is highly variable, hence clinical tests based AGFs are unlikely to have predictive value for diagnosis of PE.
Maternal oxygen delivery is not related to altitude- and ancestry-associated differences in human fetal growth
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2007) Zamudio, Stacy
Fetal growth is reduced at high altitude, but the decrease is less among long-resident populations. We hypothesized that greater maternal uteroplacental O2 delivery would explain increased fetal growth in Andean natives versus European migrants to high altitude. O2 delivery was measured with ultrasound, Doppler and haematological techniques. Participants (n = 180) were pregnant women of self-professed European or Andean ancestry living at 3600 m or 400 m in Bolivia. Ancestry was quantified using ancestry-informative single nucleotide polymorphims. The altitude-associated decrement in birth weight was 418 g in European versus 236 g in Andean women (P < 0.005). Altitude was associated with decreased uterine artery diameter, volumetric blood flow and O2 delivery regardless of ancestry. But the hypothesis was rejected as O2 delivery was similar between ancestry groups at their respective altitudes of residence. Instead, Andean neonates were larger and heavier per unit of O2 delivery, regardless of altitude (P < 0.001). European admixture among Andeans was negatively correlated with birth weight at both altitudes (P < 0.01), but admixture was not related to any of the O2 transport variables. Genetically mediated differences in maternal O2 delivery are thus unlikely to explain the Andean advantage in fetal growth. Of the other independent variables, only placental weight and gestational age explained significant variation in birth weight. Thus greater placental efficiency in O2 and nutrient transport, and/or greater fetal efficiency in substrate utilization may contribute to ancestry- and altitude-related differences in fetal growth. Uterine artery O2 delivery in these pregnancies was 99 ± 3 ml min−1, ∼5-fold greater than near-term fetal O2 consumption. Deficits in maternal O2 transport in third trimester normal pregnancy are unlikely to be causally associated with variation in fetal growth.