ORCID Profile
0000-0002-9936-5303
Current Organisation
Robert Gordon University
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Publisher: American Chemical Society (ACS)
Date: 29-06-2011
DOI: 10.1021/PR2002897
Abstract: Being born small for gestational age (SGA) confers increased risks of perinatal morbidity and mortality and increases the risk of cardiovascular complications and diabetes in later life. Accumulating evidence suggests that the etiology of SGA is usually associated with poor placental vascular development in early pregnancy. We examined metabolomic profiles using ultra performance liquid chromatography-mass spectrometry (UPLC-MS) in three independent studies: (a) venous cord plasma from normal and SGA babies, (b) plasma from a rat model of placental insufficiency and controls, and (c) early pregnancy peripheral plasma s les from women who subsequently delivered a SGA baby and controls. Multivariate analysis by cross-validated Partial Least Squares Discriminant Analysis (PLS-DA) of all 3 studies showed a comprehensive and similar disruption of plasma metabolism. A multivariate predictive model combining 19 metabolites produced by a Genetic Algorithm-based search program gave an Odds Ratio for developing SGA of 44, with an area under the Receiver Operator Characteristic curve of 0.9. Sphingolipids, phospholipids, carnitines, and fatty acids were among this panel of metabolites. The finding of a consistent discriminatory metabolite signature in early pregnancy plasma preceding the onset of SGA offers insight into disease pathogenesis and offers the promise of a robust presymptomatic screening test.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2011
DOI: 10.1161/HYPERTENSIONAHA.111.179440
Abstract: Preecl sia, a major cause of maternal and perinatal mortality and morbidity, is thought to be attributed, in part, to impaired trophoblast invasion. Peroxisome proliferator-activated receptors are ligand-activated transcription factors expressed in trophoblasts, which regulate the expression of a number of genes involved in cell differentiation and proliferation. We investigated the effect of the administration of a peroxisome proliferator-activated receptor-γ antagonist during uncomplicated pregnancy in rats. Using an intraperitoneal miniosmotic pump, healthy pregnant rats were administered either vehicle or the peroxisome proliferator-activated receptor-γ–specific antagonist, T0070907 (1 mg/kg per day from gestational days 11–15). Rats treated with T0070907 developed key features of preecl sia, including elevated mean arterial blood pressure, proteinuria, endothelial dysfunction, reduced pup weight, and increased platelet aggregation. T0070907-treated rats had reduced plasma vascular endothelial growth factor and increased plasma soluble fms-like tyrosine kinase 1. Furthermore, increases in total placental soluble fms-like tyrosine kinase 1 mRNA and fms-like tyrosine kinase 1 protein were also demonstrated, suggesting the placenta as the main contributor to the increased circulating levels of soluble fms-like tyrosine kinase 1. The labyrinthine trophoblast in the placentas of T0070907-treated rats were less differentiated, had increased cellular proliferation, and were strongly immunopositive for CD-31 staining, indicating adaptive angiogenesis. The present study suggests that peroxisome proliferator-activated receptor-γ may play a pivotal role in the progression of a healthy pregnancy and may critically regulate the risk of preecl sia. These findings have important implications regarding the underlying etiology of preecl sia and potential therapeutic targets.
Publisher: Wiley
Date: 20-02-2013
DOI: 10.1111/BPH.12069
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.PLACENTA.2011.03.010
Abstract: Preecl sia remains a leading cause of maternal and fetal morbidity and mortality and has an unknown etiology. The limited progress made regarding new treatments to reduce the incidence and severity of preecl sia has been attributed to the difficulties faced in the development of suitable animal models for the mechanistic research of this disease. In addition, animal models need hypotheses on which to be based and the slow development of testable hypotheses has also contributed to this poor progress. The past decade has seen significant advances in our understanding of preecl sia and the development of viable reproducible animal models has contributed significantly to these advances. Although many of these models have features of preecl sia, they are still poor overall models of the human disease and limited due to lack of reproducibility and because they do not include the complete spectrum of pathophysiological changes associated with preecl sia. This review aims to provide a succinct and comprehensive assessment of current animal models of preecl sia, their uses and limitations with particular attention paid to the best validated and most comprehensive models, in addition to those models which have been utilized to investigate potential therapeutic interventions for the treatment or prevention of preecl sia.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2011
DOI: 10.1161/HYPERTENSIONAHA.111.172627
Abstract: Preecl sia is a multisystemic disorder of pregnancy characterized by hypertension, proteinuria, and maternal endothelial dysfunction. It is a major cause of maternal and perinatal morbidity and mortality and is thought to be attributable, in part, to inadequate trophoblast invasion. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-activated transcription factor expressed in trophoblasts, and the vasculature of which activation has been shown to improve endothelium-dependent vasodilatation in hypertensive conditions. We investigated the effects of the administration of a PPAR-γ agonist using the reduced uterine perfusion pressure (RUPP) rat model of preecl sia. The selective PPAR-γ agonist, rosiglitazone, was administered to pregnant rats that had undergone RUPP surgery. To investigate whether any observed beneficial effects of PPAR-γ activation were mediated by the antioxidant enzyme, heme oxygenase 1, rosiglitazone was administered in combination with the heme oxygenase 1 inhibitor tin-protoporphyrin IX. RUPP rats were characterized by hypertension, endothelial dysfunction, and elevated microalbumin:creatinine ratios. Rosiglitazone administration ameliorated hypertension, improved vascular function, and reduced the elevated microalbumin:creatinine ratio in RUPP rats. With the exception of microalbumin:creatinine ratio, these beneficial effects were abrogated in the presence of the heme oxygenase 1 inhibitor. Administration of a PPAR-γ agonist prevented the development of several of the pathophysiological characteristics associated with the RUPP model of preecl sia, via a heme oxygenase 1–dependent pathway. The findings from this study provide further insight into the underlying etiology of preecl sia and a potential therapeutic target for the treatment of preecl sia.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Sarah K Walsh.