Fetal insulin and IGF-II contribute to gestational diabetes mellitus (GDM) - associated up-regolation of membrane-type matrix metalloproteinase 1 (MT1-MMP) in the human feto placental endothelium
Articolo
Data di Pubblicazione:
2012
Citazione:
Fetal insulin and IGF-II contribute to gestational diabetes mellitus (GDM) - associated up-regolation of membrane-type matrix metalloproteinase 1 (MT1-MMP) in the human feto placental endothelium / U. Hiden, L. Lassance, N.G. Tabrizi, H. Miedl, C. Tam Amersdorfer, I. Cetin, U. Lang, G. Desoye. - In: THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. - ISSN 0021-972X. - 97:10(2012 Oct), pp. 3613-3621. [10.1210/jc.2012-1212]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
C-peptide; in-vitro; growth; expression; pregnancies; cells; angiogenesis; disease; hyperglycemia; proteolysis
Elenco autori:
U. Hiden, L. Lassance, N.G. Tabrizi, H. Miedl, C. Tam Amersdorfer, I. Cetin, U. Lang, G. Desoye
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