Vascular endothelial cadherin and β-catenin in human fetoplacental vessels of pregnancies complicated by Type 1 diabetes: associations with angiogenesis and perturbed barrier function

• Published in: Diabetologia 2004-04, Vol.47 (4), p.695-709
• Main Authors: LEACH, L, GRAY, C, STATON, S, BABAWALE, M. O, GRUCHY, A, FOSTER, C, MAYHEW, T. M, JAMES, D. K
• Format: Article
• Language: English
• Subjects: Adult; beta Catenin; Biological and medical sciences; Blood Glucose - metabolism; Blotting, Western; Cadherins - metabolism; Capillary Permeability - physiology; Cytoskeletal Proteins - metabolism; Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 1 - pathology; Diabetes. Impaired glucose tolerance; Diabetic Angiopathies - pathology; Diabetic Angiopathies - physiopathology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiology; Female; Fetus - blood supply; Fluorescent Antibody Technique, Direct; Humans; Infant, Newborn; Medical sciences; Microscopy, Confocal; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - physiopathology; Phosphorylation; Placenta - blood supply; Placenta - metabolism; Placenta - physiopathology; Pregnancy; Pregnancy in Diabetics - metabolism; Pregnancy in Diabetics - pathology; Pregnancy in Diabetics - physiopathology; Pregnancy Outcome; Regional Blood Flow - physiology; Trans-Activators - metabolism
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-004-1341-7

Increased angiogenesis of fetoplacental vessels is a feature of pregnancies complicated by Type 1 diabetes mellitus, but the underlying molecular mechanisms are unknown. This investigation tests whether the diabetic maternal environment alters the phenotypic expression of placental vascular endothelial cadherin and beta-catenin, which have been implicated as key molecules in barrier formation and angiogenesis in the endothelium. Term placental microvessels from normal pregnancies (n=8) and from those complicated by Type 1 diabetes (n=8) were perfused with 76-Mr dextran tracers (1 mg/ml) and subjected to immunocytochemistry, immunoblotting and microscopy. Junctional integrity, localisation and phosphorylation were investigated along with total protein levels of vascular endothelial cadherin, beta-catenin and vascular endothelial growth factor. Stereological sampling and estimation tools were used to quantify aspects of angiogenesis and endothelial proliferation. In the Type 1 diabetic placentae, junctional localisations of vascular endothelial cadherin and beta-catenin altered significantly, with more than 50% of microvessels showing complete loss of immunoreactivity and with no overall loss of total protein. Tracer leakage was associated with these vessels. There was a two- to three-fold increase in vessels showing junctional phospho-tyrosine immunoreactivity and hyperphosphorylated beta-catenin. Vascular endothelial growth factor levels were higher in these placentae. A four-fold increase in endothelial proliferation was observed, along with an increase in total length of capillaries without any change in luminal diameter. Molecular perturbations of vascular endothelial cadherin and beta-catenin occur in fetoplacental vessels of pregnancies complicated by Type 1 diabetes. Phosphorylation and loss of these molecules from the adherens junctional domains may be influenced in part by the elevated levels of vascular endothelial growth factor in the placenta. Perturbations of the junctional proteins may explain the observed breach in barrier integrity and may contribute to the mechanisms that drive proliferation and increases in capillary length.