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62: Hyperglycemia impairs cytotrophoblast function via stress signaling

      Objective

      Diabetes mellitus is a risk factor for preeclampsia (preE). The normal extent of cytotrophoblast (CTB) invasion of the decidua, which is facilitated by plasmin, may be inhibited in preE. Inactive plasminogen is converted to plasmin by urokinase plasminogen activator (uPA), and uPA is regulated by plasminogen activator inhibitor 1 (PAI-1). Peroxisome proliferator-activated receptor gamma (PPARγ) also is implicated in the dysfunction of CTBs in hyperglycemic conditions. This study assesses the signaling mechanisms of hyperglycemia-induced CTB dysfunction.

      Study Design

      Human CTBs (Sw. 71) were treated with 45, 135, 225, 495 or 945 mg/dL glucose for 48h. Some cells were pretreated with a p38 inhibitor (SB203580) or a PPARγ ligand (rosiglitazone). Thereafter, cell lysates were utilized to measure uPA, PAI-1 and PPARγ expression and p38 Mitogen Activated Protein Kinase (MAPK) phosphorylation by western blot. The mRNA expression of uPA and PAI-1 in CTB lysates was measured by qPCR. Levels of angiogenic (soluble fms-like tyrosine kinase-1 (sFLT-1), soluble endoglin (sENG)) and anti-angiogenic factors (VEGF, PlGF) and IL-6 were measured in the culture media by ELISA.

      Results

      Both uPA and PAI-1 protein and mRNA expression were downregulated (p<0.05) in CTBs treated with >135 mg/dL glucose compared to basal (45 mg/dL). Anti-angiogenic factors (sENG, sFLT-1) and IL-6 were up-regulated, while the angiogenic factors (VEGF, PlGF) were down-regulated in the presence of >135 mg/dL glucose. The p38 MAPK phosphorylation and PPARγ expression were up-regulated (p<0.05) in hyperglycemia-exposed CTBs. SB203580 and rosiglitazone pretreatment attenuated glucose-induced down-regulation of uPA and up-regulation of p38 MAPK.

      Conclusion

      Exposure of CTBs to excess glucose inhibits the invasive profile of CTBs by decreasing the expression of uPA and PAI-1; by downregulating of VEGF and PlGF; and upregulating of sENG, sFLT-1, and IL-6. Attenuation of CTB dysfunction by SB203580 or rosiglitazone pretreatment suggests the involvement of stress signaling.