Despite medical advances, preterm delivery continues to complicate 12% of all births in the United States and is a major cause of neonatal deaths. One of the reasons that preterm labor continues to be a significant problem is that very little is understood about the factors involved in normal labor. Many investigators have studied parturition in the mouse and defined essential pathways for normal labor. Prostaglandins play an essential role in mouse labor and are important in human labor as well. We examined the 23 transcription factors from pregnant mouse uterus that change expression after the induction of cyclooxygenase-1, the enzyme that catalyzes the first committed step in prostaglandin synthesis. Using in situ hybridization, we have identified three of these transcription factors, Hoxa10, Hoxa11 and GILZ as being expressed in the decidua and regulated at the end of pregnancy. Both Hoxa10 and Hoxa11 are known to be critical for implantation, but very little is known about their roles in late gestation. GILZ has not previously been identified in the gravid uterus. In summary, we have identified three transcription factors that are regulated in the decidua at the end of pregnancy, suggesting a role in detachment of the fetus and placenta.

Background: Preterm birth is the leading cause of all infant mortality. In 2004, 12.5% of all births were preterm. In order to understand preterm labor, we must first understand normal labor. Since many of the myometrial changes that occur during pregnancy are similar in mice and humans and mouse gestation is short, we have studied the uterine genes that change in the mouse during pregnancy. Here, we used microarray analysis to identify uterine genes in the gravid mouse that are differentially regulated in the cyclooxygenase-1 knockout mouse model of delayed parturition.

Purpose of Study: Diabetes Mellitus (DM) is the most prevalent risk factor for acquiring vascular disease. Since optimal glycemic control delays onset and progression of vascular morbidities, hyperglycemia is hypothesized to be a key pathogenic factor for vasculopathies. Vascular integrity requires endothelial repair and angiogenesis. Recently, circulating endothelial progenitor cells (EPCs) were shown to have a critical role in promoting endothelial repair and angiogenesis. Given that infants exposed to a diabetic intrauterine environment have an increased risk of DM and vascular disease, we hypothesize that hyperglycemia alters neonatal EPC function. Thus, our aims were to examine the effect of hyperglycemia on newborn EPC clonogenic capacity, proliferative potential, apoptosis, senescence, and capillary tube formation. Methods Used: EPCs were isolated from multiple cord blood donors as described (Ingram et al, Blood, 104:2752, 2004) and subjected to euglycemia or hyperglycemia (10-100 mM dextrose) before conducting cellular and functional assays. Limiting dilution assays assessed EPC colony formation. Single cell assays quantitated the proportion of single EPCs capable of dividing. Proliferation potential was also assessed by population doubling studies. Apoptosis was evaluated using a TUNEL assay while senescence was examined using an acidic ␤-galactosidase method. Matrigel assays assessed capillary tube forming ability. Summary of Results: Hyperglycemia (10-100 mM) resulted in reduced EPC colony formation compared to controls (nϭ3, pϽ0.05). Hyperglycemia led to decreased EPC proliferative potential as reflected by a decrease in the number of single EPC cells dividing (nϭ96 single cells) and a lower cumulative population doubling level. In addition, increased apoptosis was detected after a 24 or 48 hour exposure to high dextrose concentrations (50mM and 100mM) compared to controls (nϭ3, pϽ 0.003). Senescence assays are underway, and preliminary matrigel assays suggest that hyperglycemia treated EPCs exhibit reduced capillary tube formation. Conclusion: These data demonstrate that neonatal EPCs have decreased clonogenic potential after hyperglycemia treatment. The mechanisms for the observed decrease in clonogenic capacity may include an increase in both apoptosis and senescence together with a decrease in proliferation. Collectively, these observations may have implications for the pathogenesis of vascular disease in diabetic patients as well as in infants exposed to a diabetic intrauterine environment. Doxorubicin, a topoisomerase II inhibitor that is commonly used to treat childhood cancer, induces p53-mediated cardiomyocyte apoptosis which can ultimately lead to heart failure. We hypothesized that cardiac-restricted expression of a dominant interfering p53 mutant (CB7) would protect cardiomyocytes from doxorubicin-induced apoptosis in vivo. Age-matched CB7 transgenic mice and control nontransgenic (NTG) mice were treated with a total of 20mg/kg of doxorubicin (2 intraperitoneal injections of 10mg/kg at 3-...