Hyperglycemia impairs cytotrophoblast function via stress signaling

Am J Obstet Gynecol. 2014 Nov;211(5):541.e1-8. doi: 10.1016/j.ajog.2014.04.033. Epub 2014 May 1.


Objective: Diabetes mellitus is a risk factor for preeclampsia. Cytotrophoblast (CTB) invasion is facilitated from the conversion of plasminogen to plasmin by urokinase plasminogen activator (uPA), regulated by plasminogen activator inhibitor 1 (PAI-1), and may be inhibited in preeclampsia. This study assessed signaling mechanisms of hyperglycemia-induced CTB dysfunction.

Study design: Human CTBs were treated with 45, 135, 225, 495, or 945 mg/dL glucose for 48 hours. Some cells were pretreated with a p38 inhibitor (SB203580) or a peroxisome proliferator-activated receptor-gamma (PPAR-γ) ligand (rosiglitazone). Expression of uPA, PAI-1, and PPAR-γ levels and p38 mitogen-activated protein kinase phosphorylation were measured by Western blot in cell lysates. Messenger ribonucleic acid of uPA and PAI-1 was measured by quantitative polymerase chain reaction. Levels of interleukin-6, angiogenic (vascular endothelial growth factor [VEGF], placenta growth factor [PlGF]) and antiangiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], soluble endoglin [sEng]) were measured in the media by enzyme-linked immunosorbent assay kits. Statistical comparisons were performed using analysis of variance with a Duncan's post-hoc test.

Results: Both uPA and PAI-1 protein and messenger ribonucleic acid were down-regulated (P < .05) in CTBs treated with 135 mg/dL glucose or greater compared with basal (45 mg/dL). The sEng, sFlt-1, and interleukin-6 were up-regulated, whereas the VEGF and PlGF were down-regulated by 135 mg/dL glucose or greater. p38 phosphorylation and PPAR-γ were up-regulated (P < .05) in hyperglycemia-treated CTBs. The SB203580 or rosiglitazone pretreatment showed an attenuation of glucose-induced down-regulation of uPA and PAI-1.

Conclusion: Hyperglycemia disrupts the invasive profile of CTB by decreasing uPA and PAI-1 expression; down-regulating VEGF and PlGF; and up-regulating sEng, sFlt-1, and interleukin-6. Attenuation of CTB dysfunction by SB203580 or rosiglitazone pretreatment suggests the involvement of stress signaling.

Keywords: angiogenesis; cell invasion; cytotrophoblast cells; hyperglycemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / drug effects
  • Antigens, CD / metabolism
  • Diabetes, Gestational / metabolism
  • Endoglin
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Glucose / pharmacology*
  • Humans
  • Hyperglycemia / metabolism*
  • Hypoglycemic Agents / pharmacology
  • Imidazoles / pharmacology
  • Interleukin-6 / metabolism
  • PPAR gamma / drug effects
  • PPAR gamma / metabolism
  • Phosphorylation / drug effects
  • Placenta Growth Factor
  • Plasminogen Activator Inhibitor 1 / genetics*
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Polymerase Chain Reaction
  • Pregnancy
  • Pregnancy Proteins / drug effects
  • Pregnancy Proteins / metabolism
  • Pyridines / pharmacology
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / metabolism
  • Rosiglitazone
  • Signal Transduction / drug effects
  • Thiazolidinediones / pharmacology
  • Trophoblasts / drug effects*
  • Urokinase-Type Plasminogen Activator / drug effects*
  • Urokinase-Type Plasminogen Activator / genetics
  • Urokinase-Type Plasminogen Activator / metabolism
  • Vascular Endothelial Growth Factor A / drug effects
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-1 / drug effects
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Antigens, CD
  • ENG protein, human
  • Endoglin
  • Hypoglycemic Agents
  • IL6 protein, human
  • Imidazoles
  • Interleukin-6
  • PGF protein, human
  • PPAR gamma
  • Plasminogen Activator Inhibitor 1
  • Pregnancy Proteins
  • Pyridines
  • Receptors, Cell Surface
  • SERPINE1 protein, human
  • Thiazolidinediones
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Rosiglitazone
  • Placenta Growth Factor
  • FLT1 protein, human
  • Vascular Endothelial Growth Factor Receptor-1
  • p38 Mitogen-Activated Protein Kinases
  • Urokinase-Type Plasminogen Activator
  • Glucose
  • SB 203580