Glucocorticoid modulation of agonist induced microvascular endothelial permeability

Abstract

AbstractPurpose Conditions such as diabetic retinopathy and neural inflammation involve microvascular barrier breakdown leading to leakage, tissue oedema and immune cell influx. Glucocorticoids(GCs) have been shown to improve the barrier function of the vasculature in retina and brain. It has been proposed that GCs function through tightening of specialized junctions between endothelial cells (ECs) and reduce paracellular permeability. We investigated the effects of hydrocortisone(HC),dexamethasone(DEX),triamcinolone(TA) and a selective glucocorticoid receptor agonist(SEGRA) on microvascular endothelial permeability induced by vascular endothelial growth factor(VEGF),lysophosphatidic acid(LPA) and histamine(Hist), all of which are proposed to be involved in diabetic and inflammatory neurovascular pathologies.Methods In vitro studies were undertaken in cultures of primary rat brain and retinal microvascular ECs, as well as a novel immortalised rat retinal EC line, PT2. Junctional protein characterisation was performed by indirect immunocytochemistry and confocal microscopy. Permeability was measured by macromolecular flux assays.Results Primary retinal and cerebral EC cultures exhibited an exquisite apico‐basal polarity in their response to vasoactive compounds, maintained high barrier properties and sophisticated junctional protein complement. Passaged or immortalised EC had lost most of these features. HC and DEX were effective in suppressing VEGF‐, LPA‐ and Hist‐induced permeability. TA results were similar, except Hist‐induced permeability was insensitive to TA. SEGRA was ineffective in preserving microvascular barrier function.Conclusion The effectiveness of GCs depends on the pathology involved in particular the vasoactive substance in play.