Doctor of Philosophy
Dr. Victor Han and Dr. Madhulika Gupta
Delay of Publication
Fetal Growth Restriction (FGR) is caused by impaired maternal-fetal exchange of oxygen and nutrients causing fetal hypoxia and starvation. A functional failure of the placenta is the underlying cause, however the pathophysiology remains unknown. The fetus adapts by limiting growth, reducing demand for metabolic substrates. Monitoring the fetal size is the primary clinical method of FGR detection, though it does not distinguish a constitutionally small fetus from a pathological. Proteomic profiling of fetal and maternal plasma was therefore undertaken for discovery of biomarkers and pathological mechanisms. As a model of hepatic secreted fetal plasma proteins, HepG2 cell secretion changes in hypoxia were also investigated. Profiling mother’s plasma revealed altered expression of vascular regulatory proteins VCAM-1 and haptoglobin. VCAM-1 positively correlated to placental size. Profiling of HepG2 secreted proteins in hypoxia revealed increased angiogenic protein PAI-1, and the growth inhibitor IGFBP-1. Fetal plasma PAI-1 levels were found to be oxygen dependent, and the levels determinant of plasma’s in vitro angiogenic potency. For IGFBP-1, increased phosphorylation was found at four discrete sites, leading to increased affinity for IGF-I, and mitigation of IGF-I stimulated cell proliferation in vitro. Increased VCAM-1 relative to placental size in FGR has potential as a marker of placental health. Fetal plasma PAI-1 levels mediating angiogenesis is a newly discovered mechanism in FGR. PAI-1’s hypoxia-dependent hepatic induction and consequent angiogenic effect may have significance to placental maldevelopment. Discovery of increased IGFBP-1 phosphorylation in hypoxia, and its inhibition of IGF-I mediated proliferation, may be an adaptive mechanism limiting fetal growth in FGR.
Seferovic, Maxim D., "Maternal and Fetal Plasma Protein Changes in Fetal Growth Restriction" (2011). University of Western Ontario - Electronic Thesis and Dissertation Repository. Paper 365.