The proposed research will test the hypothesis that the local generation and activity of nitric oxide (NO), superoxide and superoxide dismutase (SOD) regulate vascular reactivity and blood flow in the fetal-placental circulation. The rationale is based on evidence that NO is a vasodilator scavenged by superoxide, whereas SOD scavenges superoxide, hence prolonging the bioactivity of NO. Interaction of NO and superoxide produces the peroxynitrite anion, a strong long-lived cytotoxic oxidant which inhibits mitochondrial electron transport and also nitrates tyrosine residues to block tyrosine-mediated signal transduction. It is further proposed that peroxynitrite may damage the vasculature and cause endothelial dysfunction. In this regard, nitrotyrosine residues, a marker of peroxynitrite formation, are found in the fetal-placental vasculature of pregnancies complicated by preeclampsia and/or IUGR, conditions associated with increased vascular resistance as well as fetal and maternal morbidity and mortality. Based upon this evidence, the proposed research will evaluate a second hypothesis that the activity of enzymes synthesizing and metabolizing NO and superoxide is altered in preeclampsia and/or IUGR. Specifically, the investigators will determine the following: 1. The interactions of NO, superoxide, xanthine oxidase and SOD in the perfused placenta cotyledon by adding exogenous substrate, enzymes or inhibitors. 2. The direct effect of peroxynitrite on vascular reactivity in the perfused placenta and its potential to affect responses to other vasoconstrictors or vasodilators, and to compare this to reactivity of placentas from pregnancies complicated by preeclampsia and/or IUGR. 3. The presence and localization of nitrotyrosine residues in placental villous, basal plate and placental bed tissues of pregnancies complicated by preeclampsia and/or IUGR in comparison to control. 4. Formation of superoxide and peroxynitrite by tissue sections of normal and pathologic placentas and activities of xanthine oxidase and SOD enzyme isoforms in these tissues. 5. Expression of mRNA and protein for SOD isoforms, xanthine oxidase and the cytochrome b558 subunit of NADPH oxidase in normal and pathologic placental tissues using RT-PCR and immunohistochemistry.
| Myatt, L (2010) Review: Reactive oxygen and nitrogen species and functional adaptation of the placenta. Placenta 31 Suppl:S66-9 |
| Alon, Ronen; Feigelson, Sara W; Manevich, Eugenia et al. (2005) Alpha4beta1-dependent adhesion strengthening under mechanical strain is regulated by paxillin association with the alpha4-cytoplasmic domain. J Cell Biol 171:1073-84 |
| Kossenjans, W; Eis, A; Sahay, R et al. (2000) Role of peroxynitrite in altered fetal-placental vascular reactivity in diabetes or preeclampsia. Am J Physiol Heart Circ Physiol 278:H1311-9 |
| Myatt, L; Kossenjans, W; Sahay, R et al. (2000) Oxidative stress causes vascular dysfunction in the placenta. J Matern Fetal Med 9:79-82 |
