The goal of this project is to investigate potential mechanisms underling the vascular dysfunction that occurs during and after preeclampsia. Inactivation of nitric oxide (NO) by reactive oxygen species, especially superoxide (O2-), is an important mechanism of vascular dysfunction in several diseases. In this context, important links exist between angiotensin II, vascular O2-production and impaired NO-dependent relaxation. Our data has implicated angiotensin AT-1 receptor signaling and increased vascular O2-generation in the increased myogenic response and loss of endothelium-dependent relaxation that results from exposure of resistance arteries to preeclampsia plasma in vitro. Vitamin C (abscorbate) is a key modulator of NO. Plasma ascorbate is decreased during preeclampsia. In a strain of rats unable to synthesize ascorbate, we have shown that subnormal ascorbate intake (30-40% plasma reduction) during pregnancy results in a striking increase in vascular 02- output and myogenic reactivity. Therefore, we hypothesize that two phenomena associated with preeclampsia, namely 1) plasma factors interacting with the AT1 receptor, and 2) suboptimal ascorbate reserves operate in tandem to increase the prevalence of oxidative reactions within the vasculature. In turn, this leads to effective deficiency of NO, through oxidative degradation of NO and/or impaired vascular response to NO. Accordingly, we will use our isolated artery bioassay system to examine plasma factors mediated altered NO-dependent responsiveness (Aims 1 and 2).
Aim 1 is to characterize the functional changes induced by exposure of mesenteric arteries to pregnancy and postpartum plasma and to evaluate the role of candidate factors operating through angiotensin receptor subtypes.
Aim 2 is to determine the role and enzyme sources of O2-, effects of exogenous anti-oxidants and alterations in eNOS potentially impacting NO-dependent responsiveness in this model. We will also use our unique rat strain to further explore the role of ascorbate in the vascular adaptation to pregnancy (Aims 3 and 4).
Aim 3 test the hypothesis that subnormal ascorbate results in an effective deficiency of NO that is accentuated during pregnancy.
Aim 4 is to determine the oxidative mechanisms of decreased NO bioavailability in this model.
Aim 4 is to determine the oxidative mechanisms of decreased NO bioavailability in this model. This integrated approach, in combination with Subproject by S. Schroff, will provide important information concerning oxidant/anti-oxidant mediators of vascular hyperresponsiveness during and after preeclampsia.
| Global Pregnancy Collaboration:; Schalekamp-Timmermans, Sarah; Arends, Lidia R et al. (2017) Fetal sex-specific differences in gestational age at delivery in pre-eclampsia: a meta-analysis. Int J Epidemiol 46:632-642 |
| Hux, Vanessa J; Roberts, James M; Okun, Michele L (2017) Allostatic load in early pregnancy is associated with poor sleep quality. Sleep Med 33:85-90 |
| Countouris, Malamo E; Schwarz, Eleanor B; Rossiter, Brianna C et al. (2016) Effects of lactation on postpartum blood pressure among women with gestational hypertension and preeclampsia. Am J Obstet Gynecol 215:241.e1-8 |
| Gandley, Robin E; Althouse, Andrew; Jeyabalan, Arundhathi et al. (2016) Low Soluble Syndecan-1 Precedes Preeclampsia. PLoS One 11:e0157608 |
| Schmella, Mandy J; Clifton, Rebecca G; Althouse, Andrew D et al. (2015) Uric Acid Determination in Gestational Hypertension: Is it as Effective a Delineator of Risk as Proteinuria in High-Risk Women? Reprod Sci 22:1212-9 |
| Luiza, John W; Gallaher, Marcia J; Powers, Robert W (2015) Urinary cortisol and depression in early pregnancy: role of adiposity and race. BMC Pregnancy Childbirth 15:30 |
| Hux, Vanessa J; Roberts, James M (2015) A potential role for allostatic load in preeclampsia. Matern Child Health J 19:591-7 |
| Hassis, Maria E; Niles, Richard K; Braten, Miles N et al. (2015) Evaluating the effects of preanalytical variables on the stability of the human plasma proteome. Anal Biochem 478:14-22 |
| Catov, Janet M; Abatemarco, Diane; Althouse, Andrew et al. (2015) Patterns of gestational weight gain related to fetal growth among women with overweight and obesity. Obesity (Silver Spring) 23:1071-8 |
| Founds, Sandra A; Ren, Dianxu; Roberts, James M et al. (2015) Follistatin-like 3 across gestation in preeclampsia and uncomplicated pregnancies among lean and obese women. Reprod Sci 22:402-9 |
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