Altered liver secretion of vascular regulatory proteins in hypoxic pregnancies stimulate angiogenesis in vitro

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Journal titleJournal of Proteome Research
Pages14951504; # of pages: 10
Subjectclusterin; plasminogen activator inhibitor 1; regulator protein; transferrin; unclassified drug; vascular regulatory protein; angiogenesis; article; birth weight; cell culture; cell strain HepG2; densitometry; endothelium cell; fetus blood; gestational age; human; human cell; immunoassay; in vitro study; intrauterine growth retardation; oxygen blood level; priority journal; protein secretion; Angiogenic Proteins; Birth Weight; Female; Fetal Growth Retardation; Fetal Hypoxia; Fetus; Gestational Age; Hep G2 Cells; Humans; Infant, Newborn; Liver; Male; Neovascularization, Physiologic; Oxygen; Pregnancy; Pregnancy Complications; Proteome; Tandem Mass Spectrometry; Two-Dimensional Difference Gel Electrophoresis
AbstractPlacental vascular malformations result in fetal hypoxia, a serious pregnancy complication. Recent studies have linked liver-secreted and hemostatic proteins with angiogenesis. We therefore evaluated liver protein secretion changes following hypoxia, and their effect on angiogenesis, to identify potential angiogenic protein changes in the plasma of hypoxic newborns. Human vascular endothelial cells exhibited 10-fold increased tube formation with secretions from HepG2 cells cultured in 1% O 2 and 3-fold in 4% O 2 (p < 0.0001, p < 0.05) compared to 20% O 2. 2-DGE profiling of the secretions revealed significant density changes (p < 0.05) in spots identified as angiogenic proteins by LC-MS/MS. Clusterin decreased (-1.6-fold), whereas two spots of plasminogen activator inhibitor-1 (PAI-1) (2.4, and 3.6-fold), and three spots of transferrin (1.3, 1.5, and 2.6-fold) increased with 1% O 2. The levels of these proteins, subsequently determined in fetal plasma by immunoassays, strongly correlate with the fetal blood oxygen level at birth; PAI-1 and transferrin increase with low venous pO 2 (r = -0.70, p = 0.02, and r = -0.66, p = 0.04), clusterin and fibrinogen decrease (r = 0.82, p = 0.002, and r = 0.70, p = 0.02). These findings demonstrate that low oxygen levels in utero lead to pro-angiogenic changes in liver secreted plasma proteins. The pro-vascular plasma environment in hypoxic pregnancies may be acting to mitigate the compromised vasculature. © 2011 American Chemical Society.
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AffiliationNational Research Council Canada (NRC-CNRC); NRC Institute for Marine Biosciences (IMB-IBM)
Peer reviewedYes
NPARC number21271543
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Record identifier2e1f1ace-1fc8-4da8-a320-bd0eaeb389c8
Record created2014-03-24
Record modified2016-05-09
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