Effects of gestational diabetes on junctional adhesion molecules in human term placental vasculature

Abstract

The human placenta is a highly vascularised organ whose major functions are to allow materno-fetal exchange of solutes and oxygen. Formation of the placental fetal vessels (vasculogenesis) occurs in the first 4 weeks of pregnancy and elaboration of the microvascular beds (angiogenesis) occurs in the last trimester of pregnancy. The structure and permeability of these vessels, at term, resemble those of skeletal muscle capillaries [1,2]. Both vascular remodelling and effective barrier formation are key endothelial functions, which influence fetal well-being and perinatal outcome. One of the major complications in pregnancies is diabetes mellitus. In pregnancies in women with pre-existing diabetes, both vasculogenesis and angiogenesis, in theory, can be affected. Ges- Diabetologia (2000) Abstract Aims/hypothesis. The aim of this study was to investigate whether gestational diabetes mellitus, which occurs in the microvascular remodelling phase of placental development, causes alterations in surface expression of tight and adherens junctional molecules involved in endothelial barrier function and angiogenesis.Methods. Term placenta, delivered by elective Caesarian section, from normal pregnancy (n = 5) and those complicated by gestational diabetes (n = 5) were perfusion-fixed and analysed by indirect immunofluorescence and confocal scanning microscopy. Using systematic random sampling, the surface expression of endothelial junctional proteins and the relative incidences of immunostained vessels were compared between the two study groups. Total vessel lengths were measured by stereological techniques.Results. The adherens junctional molecules, vascularendothelial cadherin and b-catenin, and the tight junctional molecules, occludin and zonula occludens-1 were localised to paracellular clefts in both study groups. The diabetic placentae showed pronounced reductions in the intensity of immunofluorescence and in the number of immuno-positive vessels. A corresponding statistically significant increase (from 19 % to 56 %) in the percentage of vessels showing junctional anti-phosphotyrosine immunoreactivity was found. The differences observed represented real changes in the absolute lengths of immunostained regions along the vessels. The stereological measurements failed to detect any statistically significant change in the combined length of fetal vessels in gestational diabetic placenta. Conclusion/interpretation. Our results suggest that even short duration diabetic insult, alters the surface expression of placental junctional proteins. This alteration could be mediated by the tyrosine-phosphorylation pathway. The changes suggest impaired barrier function rather than accelerated vascular growth.

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

“…In gestational diabetes (which affects the latter half of pregnancy, sparing the development stages of vas-culogenesis and early angiogenesis) the picture is less clear, since there is junctional perturbation [23] but also evidence for and against enhanced angiogenesis [23,48]. Since some of these pregnancies may have included pre-gestational Type 2 diabetes patients, further investigations on gestational diabetes are required to resolve the apparent discrepancies.…”

“…The relative incidences of vascular profiles showing different junctional immunoreactivities were estimated as described previously by applying random sampling procedures and unbiased profile counting rules [23,28]. Provided that encounters between section planes and vessels occur at random orientations, these two-dimensional counts also represent the relative lengths in three dimensions of immunostained regions along the entire length of the vascular bed.…”

“…As described previously [23], to minimise shrinkage and processing distortions, toluidine blue-stained semi-thin resin sections of placenta were used. Systematic random sampling of fields was achieved using an Olympus microscope (Olympus Danmark, Silkborg, Denmark) with a motorised stage controlled by x-y axis step motors.…”

“…Certainly, short-duration diabetes, such as gestational diabetes, does result in significant loss of surface expression of junctional adhesion molecules [23]. The possible functional consequences of such alterations, e.g.…”

Placental virtual biopsy: 3D-US hemodynamics of normal pregnancy versus gestational diabetes

“…For this reason, the evaluation of conventional funicular-Doppler does not have a predictive value in gestational diabetes. However, placentas in this type of pregnancies present hystological alterations, showing a significant decrease of the number of blood vessels [1][2][3] . The search for placental hemodynamic markers may be a good method for the prediction of the metabolic condition of these fetuses, no matter the degree of oxygenation, and for establishing an early prognosis [4][5][6][7] .…”