Fetal insulin and IGF-II contribute to gestational diabetes mellitus (GDM)-associated up-regulation of membrane-type matrix metalloproteinase 1 (MT1-MMP) in the human feto-placental endothelium.
BACKGROUND
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.


METHODS
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.
Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria. ursula.hiden@medunigraz.at
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Hiden
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Lassance
N Ghaffari
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Tabrizi
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Miedl
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Tam-Amersdorfer
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Cetin
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Lang
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Desoye
D000328:Adult; D016640:Diabetes, Gestational / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology; D010920:Placenta / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D011263:Pregnancy Trimester, Third / Q000378:metabolism; D061251:Primary Cell Culture; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D007328:Insulin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D005947:Glucose