Glucocorticoid effects on mouse microvascular endothelial barrier permeability are brain specific

Abstract

Endothelial cells (ECs) from different vascular beds display certain common qualities, but each subtype is uniquely adapted to meet the demands of the underlying tissues. The structural peculiarities of intercellular junctions are, for instance, considered to account for the differences in permeability displayed by various vascular beds: strong occludin expression is unique to cerebral ECs and considered to account for the high electrical resistance and low paracellular permeability of brain microvessels which constitute the blood-brain barrier (BBB). The integrity of the BBB is compromised in many disorders of the human CNS; therapeutic strategies include treatment with glucocorticoids (GCs), which improve barrier properties of the BBB. In contrast, positive effects of GCs on peripheral vascular permeability could not be demonstrated clearly, while side-effects of prolonged GC treatment are considerable. In an effort to elucidate this difference, we analysed the expression of occludin and the glucocorticoid receptor (GR) in BBB and non-BBB (myocardium) endothelial cells. Our results demonstrate complete GR downregulation by GCs in murine non-BBB endothelial cells in vivo, whereas GC administration led to nuclear concentration of GRs in BBB endothelium. In correlation with these in vivo data, the use of cerebral and myocardial endothelial cell lines proved GR downregulation in non-BBB cells in vitro in response to GC treatment. Divergent transactivating activity of GRs in the BBB and non-BBB endothelial cellular context could be demonstrated after transfection of endothelial cells with a model GC-responsive test promoter plasmid in the presence and absence of dexamethasone. Our results thus suggest differential signalling mechanisms involved in endothelial barrier regulation, arguing for the development of tissue-specific drugs for therapeutic applications.

Effects of prednisolone on the dystrophin-associated proteins in the blood–brain barrier and skeletal muscle of dystrophic mdx mice

“…In fact, binding of the activated glucocorticoid receptor to putative glucocorticoid-responsive elements in the occludin promoter has been described. 38,59,60 Dexamethasone prevents alteration of TJ-associated proteins in bacterially infected epithelial choroidal cells by restoring the occludin phosphorylation degree via attenuation of ERK activation and MMP-3 expression. 61 It is noteworthy that the inhibition of the ERK pathways blocks the production of MMPs, which in Prednisolone in mdx mice R Tamma et al turn cleave occludin in the epithelial cells after induced apoptosis.…”

Glucocorticoids in the control of neuroinflammation

“…Direct effects of GCs on the BBB were demonstrated in vitro (Figure 2). In cultured brain endothelial cells dexamethasone induced the reduction of pores, the concentration of F-Actin on the cell periphery and an increased expression of ZO-1 and occludin (Förster et al, 2005;Förster et al, 2006;Romero et al, 2003). How these mechanisms impact the integrity of the BBB in vivo requires A c c e p t e d M a n u s c r i p t -10 further investigation.…”

Setting-up an <em>In Vitro</em> Model of Rat Blood-brain Barrier (BBB): A Focus on BBB Impermeability and Receptor-mediated Transport

“…Before co-culture establishment, astrocytes were exposed to differentiation medium containing the glucocorticoid receptor agonist hydrocortisone, and co-culture conditioned medium. Hydrocortisone is known to improve the tightness of brain endothelial cells and is used in BBB models especially from rat 57 and mouse 58,59 endothelial cells. The conditioned medium is collected from the lower compartment of the endothelial cell/astrocyte co-culture system after 3 days and frozen for later use.…”