No abstract

Breakdown of the blood-brain barrier is a feature of acute and chronic neurodegenerative changes, yet the relationship between astrocytes and the mature barrier remains unclear. We studied this role of astrocytes in vivo using a gliotoxin and evaluated changes in three vascular tight junction markers. Male Fisher F344 rats given systemic 3-chloropropanediol showed astrocytic loss in the inferior colliculus from 12-24 h until the lesion was repopulated 8-28 days later. Within 6 h of astrocyte loss, microvessels in this area began to demonstrate a loss of the normal paracellular localization of the transmembrane proteins occludin and claudin-5 and cytoplasmic zonula occludens-1, which correlated with focal vascular leak of dextran (10 kDa) and fibrinogen. Platelet endothelial adhesion molecule-1 staining revealed that there was no loss of the endothelial lining. Between 4-8 days, severe downregulation of tight junction protein expression was observed, which subsequently returned over the same time period as astrocytes repopulated the lesion. Unexpectedly, dextran and fibrinogen leak from vessels had ceased at 6 days, well before the return of occludin and claudin-5 to appropriate paracellular domains. Control nonvulnerable cortical tissue showed no change in astrocyte morphology and tight junction expression over the same time course. Our data supports a primary role for astrocytic contact in the expression of occludin, claudin-5, and zonula occludens-1 in the mature brain vasculature in vivo. However, barrier integrity to dextran (10 kDa) and fibrinogen can be restored in the absence of astrocytes and tight junction proteins (occludin, claudin-5, and zonula occludens-1).

In the human placenta, the angioarchitecture of fetal vessels lying in maternal blood is useful for nutrient uptake, but it makes the synthesis, maturation and functioning of placental vessels vulnerable to any alterations in the fetal and maternal environment. This review discusses how the maternal diabetic milieu, and the resultant fetal hyperglycemia and hyperinsulinemia, may act together to produce an altered placental vascular phenotype, which includes increased angiogenesis, altered junctional maturity, increased vascular endothelial-like growth factor (VEGF), altered VEGF and insulin receptor profiles, and upregulation of genes involved in signal transduction, transcription and mitosis in placental endothelial cells. The placental vascular dysfunction does extend to other fetal vascular beds including endothelial cells from umbilical vessels, where there are reports of elevated basal iNOS activity and altered sensitivity to insulin. There is emerging evidence of epigenetic modulation of fetal endothelial genes in diabetes and long-term vascular consequences of this. Thus, placental vascular dysfunction in diabetes may be contributing to and describing disturbances in the fetal vasculature, which may produce an overt pathological response in later life if challenged with additional cardiovascular stresses.