Vascular dysfunction in the diabetic placenta: causes and consequences

Abstract

The development and functioning of the human fetoplacental vascular system are vulnerable to the maternal diabetic milieu. These vessels are in direct continuum with the fetal vascular system and are therefore also vulnerable to fetal endocrine derangements. Increased angiogenesis, altered junctional maturity and molecular occupancy, together with increased leakiness, constitute a well-described phenotype of vessels in the Type 1 diabetic human placenta and can be related to increased levels of placental vascular endothelial growth factor. The causes of these observed changes, whether maternal hyperglycaemia or fetal hyperinsulinaemia, still remain to be shown in the human placenta. Mechanistic studies using different vascular systems have shown high glucose and insulin to have profound vascular effects, with elevations in vascular endothelial growth factor, nitric oxide and protein kinase C being behind alterations in junctional adhesion molecules such as occludin and vascular endothelial-cadherin and vascular leakage of albumin. The role of advanced glycation products and oxidative stress in this vascular pathology is also discussed. The altered molecular mechanisms underlying the vascular changes in the diabetic human placenta may reflect similar consequences of high glucose and hyperinsulinaemia.

Fig. 1

Schematic diagram of key tight and adherens junctional adhesion molecules in quiescent mature endothelial paracellular clefts. Tight junctions here also include the endothelial junctional molecule (JAM)-A. This arrangement of linking molecules allows stabilization at specific membrane domains ensuring that the shape and polarity of the endothelial cell is maintained and the opening and closing of the cell junctions can be regulated.

Fig. 2

Schematic diagram showing how VEGF may disrupt adherens junctions, the major regulator of paracellular permeability in human placental exchange vessels. Occupation of VEGFR-2 by VEGF may lead to autophosphorylation of VE-cadherin with loss of anchorage to actin, declustering and translocation of VE-cadherin and β-catenin. This would alter cleft dimension and paracellular filter properties, affecting rate of transfer and allowing transport of larger hydrophilic proteins.