Men-Jean Lee

Glucocorticoid Enhances Transforming Growth Factor-β Effects on Extracellular Matrix Protein Expression in Human Placental Mesenchymal Cells

Abstract Extracellular matrix (ECM) proteins synthesized by human placental mesenchymal cells (PMCs) provide structural support for the villus. Aberrant expression of ECM proteins by PMCs has been associated with intrauterine growth restriction (IUGR). To provide insight into the mechanisms of ECM protein regulation in the stroma of the placental villus, in the current study, we examined the interaction of glucocorticoid (GC) and transforming growth factor-β (TGFβ) in the modulation of ECM proteins in cultures of PMCs isolated from human term placentas. Initial results obtained by ELISA showed that combined treatment with dexamethasone (DEX) and TGFβ enhanced oncofetal fibronectin (FFN) protein levels in serum-free culture medium severalfold in a dose-dependent manner. Northern blotting and real-time polymerase chain reaction (PCR) analyses revealed a similar enhancement in levels of FN mRNA in cells treated with TGFβ and DEX. Real-time PCR results also revealed that DEX and TGFβ enhanced collagen (Col) I and Col IV expression, but did not affect levels of Col III or laminin, indicative of selective stimulation of ECM proteins. Hypoxic treatment moderately enhanced FFN levels in control cells but not in those treated with DEX and TGFβ. In contrast with the results obtained with PMCs, we noted that DEX treatment suppressed FFN levels in untreated and TGFβ-treated cytotrophoblasts, suggesting that GC and TGFβ modulate FFN expression in placenta in a cell-type-specific manner. We conclude that GC and TGFβ are key regulators of ECM protein synthesis in PMCs, suggesting a role in modulating placental architecture in uncomplicated pregnancies and those associated with aberrant ECM protein expression.

Does raising the glucose challenge test threshold impact birthweight in Asian gravidas

Abstract Objective: Some authors suggest a glucose challenge test (GCT) threshold of 150 mg/dL in Asian gravidas. The impact of such a policy on outcomes is unknown. Study Design: A retrospective cohort of 1705 Asian gravidas. Subjects (n=95) had a GCT of 140–150 mg/dL and underwent a 3-h glucose tolerance test (GTT). Matched controls (n=190) had a GCT of <140 mg/dL. Birthweight was the primary outcome and the secondary outcomes were cesarean delivery (CD) rate and macrosomia. Results: Eight subjects (11.9%) had gestational diabetes mellitus (GDM); none had GTT fasting values of >90 mg/dL. Mean birthweight was 3282 g in the subjects and 3238 g in the controls (P=0.39). There were no significant differences in the secondary outcomes. Conclusion: Compared with controls, study patients did not deliver significantly larger infants. However, raising the GCT threshold would have missed 8 subjects (11.9%) with GDM. Raising the GCT threshold to 150 mg/dL in Asian gravidas may unacceptably lower the sensitivity of the screening test.

Potential Role of Glucocorticoids in the Pathophysiology of Intrauterine Growth Restriction (IUGR)

Although the etiology of intrauterine growth restriction (IUGR) and preeclampsia (PE) remains unclear, most investigators attribute the initial “insult” to poor utero-placental perfusion due to defective trophoblast invasion that ultimately compromises fetal well-being.1, 2, 3 The resultant hypoxia curtails the remodeling of uterine vessels by invasive cytotrophoblasts in the second trimester.1,2 Our results suggest that mediators of fetal stress [i.e., glucocorticoids (GC)] may in fact alter placental gene expression and contribute to the destruction of the placental villous network in pregnancies with IUGR/PE. We will present a molecular model through which GC, induced in response to fetal stress, promotes the placental villous damage observed in pregnancies associated with IUGR/PE. This model incorporates the roles of trophoblast plasminogen activator inhibitor (PAI)-l, mesenchymal extracellular matrix (ECM) proteins, and their regulation by transforming growth factor (TGF)-β. We will employ the term “IUGR/PE” to describe those pregnancies with severely growth-restricted fetuses may also complicated by maternal PE These conditions frequently coexist, and a review of the literature suggests that this placental pathology may be associated with both IUGR and PE. Furthermore, considerable attention has been given to the role of exogenously administered and stress-induced endogenous increases in fetal GC and the development of IUGR. There is mounting evidence that aberrant elevations in GC during fetal life and/or IUGR may result in fetal programming of chronic diseases of adulthood such as diabetes, coronary artery disease, and hypertension.