American Journal of Obstetrics and Gynecology
ResearchObstetricsHyperglycemia impairs cytotrophoblast function via stress signaling
Section snippets
CTB cell culture
The human extravillous CTB cell line Sw.71 utilized in these studies was derived from first-trimester chorionic villus tissue and was kindly provided by Dr Gil G. Mor (Yale University School of Medicine, New Haven, CT). These cells are well characterized and share many characteristics with isolated primary cells, including the expression of cytokeratin-7, human leukocyte antigen class I antigen, human leukocyte antigen-G, BC-1, CD9, human chorionic gonadotropin, and human placental lactogen.
Hyperglycemia up-regulated p38 MAPK phosphorylation and PPAR-γ expression
Figure 2 demonstrates that the ratio of phosphorylated p38 MAPK to the nonphosphorylated p38α/β was significantly (P < .05) up-regulated in all the CTB cell cultures treated with 495 mg/dL or more of glucose compared with basal (45 mg/dL). Intermediate levels of glucose exposure, beginning at more than 225 mg/dL, produced intermediate changes that were not different from values at either exposure to 45 mg/dL or 495 mg/dL. In addition, Figure 2 shows that PPAR-γ expression was significantly
Comment
As confirmed by multiple other investigators, preeclampsia is commonly associated with inadequate endovascular cytotrophoblast function.8, 9 Postulating supraphysiological hyperglycemia as an environmental stressor, we demonstrate an induction of PPAR-γ expression that is consistent with that reported by Suwaki et al42 yet differing with Jawerbaum et al.43 These results also are consistent with those reported by Zhou et al,40 who illustrated that hyperglycemia activates multiple MAPK pathways
References (47)
- et al.
Review: biochemical markers to predict preeclampsia
Placenta
(2012) - et al.
Pathogenesis of preeclampsia: marinobufagenin and angiogenic imbalance as biomarkers of the syndrome
Transl Res
(2012) - et al.
Invasive trophoblasts stimulate vascular smooth muscle cell apoptosis by a fas ligand-dependent mechanism
Am J Pathol
(2006) Plasminogen activators, integrins and the coordinated regulation of cell adhesion and migration
Cur Opin Cell Biol
(1997)- et al.
Expression of the urokinase, plasminogen activator inhibitors and urokinase receptor in pregnant rhesus monkey uterus during early placentation
Placenta
(2000) - et al.
Organization and regulation of mitogen-activated protein kinase signaling pathways
Curr Opin Cell Biol
(1999) - et al.
p38 MAP kinases: beyond the stress response
Trends Biochem Sci
(2000) - et al.
Examination of the cellular mechanisms by which marinobufagenin inhibits cytotrophoblast function
J Biol Chem
(2008) - et al.
PPARgamma is required for placental, cardiac, and adipose tissue development
Mol Cell
(1999) - et al.
PPARgamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance
Mol Cell
(1999)
The 15-deoxy-D12.14-prostaglandin J2 receptor, peroxisome proliferator-activated receptor-gamma (PPARgamma) is expressed in human gestational tissues and is functionally active in JEG3 choriocarcinoma cells
Placenta
Angiotensin-(1–7) attenuates high glucose-induced proximal tubular epithelial-to-mesenchymal transition via inhibiting ERK1/2 and p38 phosphorylation
Life Sci
Marinobufagenin inhibits proliferation and migration of cytotrophoblast and CHO cells
Placenta
Expression and potential role of peroxisome proliferator-activated receptor g in the placenta of diabetic pregnancy
Placenta
Preeclampsia and the anti-angiogenic state
Pregnancy Hypertens
Preeclampsia. Part I: clinical and pathophysiological considerations
Obstet Gynecol Surv
Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women
Diabetologia
Diabetes mellitus and preeclampsia
Med J Obstet Gynecol
The placenta in pregnancy hypertension
Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy
Am J Obstet Gynecol
Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts
J Clin Invest
Human cytotrophoblasts adopt a vascular phenotype as they differentiate: a strategy for successful endovascular invasion?
J Clin Invest
The role of the spiral arteries in the pathogenesis of preeclampsia
Obstet Gynecol Annu
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This study was supported by the Scott, Sherwood, and Brindley Foundation, Department of Obstetrics and Gynecology (M.N.U.), and the Noble Centennial Endowment for Research in Obstetrics and Gynecology (T.J.K.), Scott and White Healthcare, Temple, TX.
The authors report no conflict of interest.
Cite this article as: Cawyer CR, Horvat D, Leonard D, et al. Hyperglycemia impairs cytotrophoblast function via stress signaling. Am J Obstet Gynecol 2014;211:541.e1-8.