Tag: Jeffrey Gilbert

Pravastatin Attenuates Preeclamptic-like Symptoms in Rat Model of Pregnancy-Induced Hypertension

Presenter: Haley Gillham

Mentor: Jeffrey Gilbert

AM Poster Presentation

Poster 11

Preeclampsia is a pregnancy-specific condition characterized by an imbalance of circulating angiogenic factors and new onset hyper- tension. Although current treatment options are limited, recent studies suggest pravastatin may improve the angiogenic profile and reduce blood pressure in preeclampsia. We hypothesized pravastatin administration would increase VEGF and reduce arterial pressure (AP) in rats with reduced utero-placental perfusion pressure (RUPP)-induced hypertension. On day 14 of pregnancy (21-day term), silver clips were placed on the inferior abdominal aorta and ovarian arteries to generate RUPP-hypertension. Pravastatin (RUPP+P) was administered i.p. (1 mg/kg/day) through day 19. On day 19 AP was measured via catheter and conceptus data recorded. Blood pressure was increased (P<0.05) in RUPP compared to normal pregnant (NP) dams and pravastatin ameliorated this difference (118±3 vs 91±2 vs 109±2 mmHg). RUPP decreased plasma VEGF when compared to NP dams and this was attenuated by pravastatin (759.8±52.3 vs 924.1±43.6 vs 969.5±85.3 pg/mL; P<0.05). To identify the exact role of pravastatin in restoring angiogenic balance in placental ischemia we will perform further experiments in placental cell lines JAr, JEG-3, and BeWo. These cells will be treated with physiological hypoxic, normoxic, and supraoxic oxygen concentrations of 1.5%, 8%, and 20% respectively. Cells will be treated with pravastatin (0, 10, 20 μmol/L) and samples of conditioned media and cells will be taken at 0 hours, 6 hours, and 12 hours.

Effects of Metformin on pro- and anti-angiogenic factor secretion by placental trophoblast cells

Presenter: Susan Capoccia

Mentor: Jeffrey Gilbert

AM Poster Presentation

Poster 7

Maternal endothelial dysfunction, a primary characteristic of hypertension during preeclampsia is thought to arise from excess production of anti-angiogenic factors such as soluble fms-like tyrosine-1 (Sflt-1) and soluble endoglin (sEng), by the ischemic placenta. We and others have reported increased levels of sFlt-1 and sEng in rats with reduced uteroplacental perfusion pressure (RUPP) -induced hypertension and in preeclampsia. While our lab has recently found administration of an adenosine monophosphate kinase (AMPK) pathway agonist restores VEGF levels in the RUPP rats and attenuates angiogenic imbalance, the exact mechanism underlying this observation remains unclear. We hypothesize that stimulating the AMPK pathway via metformin (MET) will attenuate hypoxia- induced increases in sEng and sFlt-1 and promote VEGF secretion. Placental cells were incubated at 20% O2, physiological normoxic 8% O2 and hypoxic 1.5% O2, and treated with MET at 0mM, 50mM and 500mM for 12 and 24 hour periods. Our findings show MET increased VEGF and sENG in JEG cells at all O2 concentrations. sEng levels increased in the hypoxic JAR cells compared to 20 % O2 and 8% O2 and MET decreased these levels. Further studies will determine if the placental MET induced AMPK signaling pathways are similar to those in skeletal muscle. Although MET had differential effects on placental cells, the overall ratio of angiogenic factors may be restored, leading to angiogenic balance and relief of endothelial dysfunction via stimulation of the AMPK pathway.

Altered Lung Development in Growth Restricted Offspring from Hypertensive Pregnant Rats

Presenter : Alice Rear

Mentor : Jeffrey Gilbert

Major : Biology and Human Physiology

Poster 37

Recent studies suggest that angiogenic dysregulation in utero impairs fetal pulmonary vascular development and arrests normal alveolarization, potentially contributing to the pathogenesis of bronchopulmonary dysplasia (BPD). Since reduced utero-placental perfusion (RUPP) induced hypertension is associated with angiogenic imbalance (soluble fms-like tyrosine kinase-1, sFlt-1; and vascular endothelial growth factor, VEGF) in the maternal circulation and amniotic fluid, we hypothesized it would result in abnormal alveolarization, diminished pulmonary vascular development, and impaired VEGF signaling in the fetal rat lung. Fetal lung tissue and amniotic fluid were collected on day 19 of gestation from RUPP and normal pregnancies (NP). A second cohort delivered pups that were weighed at birth and lungs were collected at 10 weeks of age. Fetuses from RUPP pregnancies were smaller at day 19 (2.1 vs. 2.6 g; P<0.05) of gestation and at birth (6.1 vs. 6.7 g; P<0.05) than NP offspring. Preliminary data suggests that RUPP offspring may have reduced (20% decrease) pulmonary vascularity and alveolar simplification (45% decrease in alveolar space) when compared to normal pregnant controls. VEGF receptor-2 was decreased (48%; P< 0.05) in the lungs of day 19 RUPP offspring. These data suggest that chronic placental insufficiency has detrimental effects on the developing pulmonary vasculature and alveoli, and support the hypoth- esis that angiogenic imbalance in utero may play an important role in the pathogenesis of BPD

AICAR Administration Promotes a Cytoprotective and Pro-Angiogenic Stimulation in an Ex Vivo Model of Placental Ischemia

Presenter : Sarah Johnson

Mentor : Jeffrey Gilbert

Major : Biology/Human Physiology

Poster 28

The pregnancy-specific hypertension known as preeclampsia (PE) is widely observed worldwide and is recognized as a leading contributor to sickness and death of a mother and her baby. This pervasive condition is yet to be fully characterized, as is an effective therapy of symptom relief outside of inducing early delivery. We have recently reported treatment with an adenosine-mimetic, AICA-riboside (AICAR), in an experimental model of PE reduces the onset of PE-like characteristics; however, the underlying mechanisms are poorly understood. Therefore, our hypothesis was AICAR would initiate cytoprotective and pro-angiogenic stimulation in cultured placental tissue explants, and this effect would be mediated by the adenosine (ENT1/2) transporter. Tissues were cultured at 37°C for 12 hours in physiologic normoxic (8% O2) or hypoxic (1.5% O2) conditions, and treated with AICAR (2mM) and an adenosine transporter blocker (dipyridamole, DPM) (100μM). Explants treated with AICAR exhibited a decreased (P<0.05) secreted sFlt-1 in both O2 conditions, and DPM blocked this effect. The energy regulatory protein AMPKα phosphorylation was elevated in the tissues treated with AICAR, but was not statistically significant (0.1>P>0.05). Through modeling placental ischemia ex vivo, we have demonstrated AICAR decreas- es placental secretion of sFlt-1, mediated by adenosine transport activity. In concert with our previous in vivo studies with AICAR, this study further supports a placental specific mechanism of AICAR’s actions in vivo.