Abstract

CONTEXT
Gestational diabetes mellitus (GDM)-associated hormonal and metabolic derangements in mother and fetus affect placental development and function. Indeed, in GDM, placentas are characterized by hypervascularization and vascular dysfunction. The membrane-type matrix metalloproteinase 1 (MT1-MMP) is a key player in angiogenesis and vascular expansion.
OBJECTIVE
Here, we hypothesized elevated placental MT1-MMP levels in GDM induced by components of the diabetic environment. Therefore, we measured placental MT1-MMP in normal vs. GDM pregnancies, identified potential functional consequences, and investigated the contribution of hyperglycemia and the insulin/IGF axis.
DESIGN
Immunohistochemistry identified placental cell types expressing MT1-MMP. MT1-MMP was compared between normal and GDM placentas by immunoblotting. Quantitative PCR of MT1-MMP in primary feto-placental endothelial cells (fpEC) and trophoblasts isolated from both normal and GDM placentas identified the cells contributing to the GDM-associated changes. A putative MT1-MMP role in angiogenesis was determined using blocking antibodies for in vitro angiogenesis assays. Potential GDM-associated factors and signaling pathways inducing MT1-MMP up-regulation in fpEC were identified using kinase inhibitors.
RESULTS
Total and active MT1-MMP was increased in GDM placentas (+51 and 54%, respectively, P<0.05) as a result of up-regulated expression in fpEC (2.1-fold, P=0.02). MT1-MMP blocking antibodies reduced in vitro angiogenesis up to 25% (P=0.03). Pathophysiological levels of insulin and IGF-II, but not IGF-I and glucose, stimulated MT1-MMP expression in fpEC by phosphatidylinositol 3-kinase signals relayed through the insulin, but not IGF-I, receptor.
CONCLUSIONS
GDM up-regulates MT1-MMP in the feto-placental endothelium, and insulin and IGF-II contribute. This may account for GDM-associated changes in the feto-placental vasculature.

Links

Publisher Full Text

Authors

Hiden U, Lassance L, Tabrizi NG, Miedl H, Tam-Amersdorfer C, Cetin I, Lang U, Desoye G

Institution

Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria. ursula.hiden@medunigraz.at

Source

The Journal of clinical endocrinology and metabolism 97:10 2012 Oct pg 3613-21

MeSH

Adult
Diabetes, Gestational
Endothelial Cells
Female
Fetus
Glucose
Humans
Hyperglycemia
Insulin
Insulin-Like Growth Factor I
Insulin-Like Growth Factor II
Matrix Metalloproteinase 14
Neovascularization, Physiologic
Placenta
Pregnancy
Pregnancy Trimester, Third
Primary Cell Culture
Trophoblasts
Up-Regulation

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22893718