Endocrine Abstracts (2009) 19 OC13

Inhibition of 11[beta]-hydroxysteroid dehydrogenase type 1 promotes intra-retinal vascularisation in a murine model of ischaemic retinopathy

A Dover1, A Stitt2, C McVicar2, C Kitson2, P Hadoke1 & B Walker1

1University of Edinburgh, Edinburgh, UK; 2Queen’s University, Belfast, UK.

Glucocorticoids possess potent angiostatic properties. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) amplifies local glucocorticoid action in a tissue-specific manner, and we have shown that inactivation of this enzyme enhances angiogenesis within sponges implanted subcutaneously, wounds and infarcted myocardium. 11βHSD1 is present within ocular tissues but its role in the pathogenesis of proliferative retinopathy is unknown. We hypothesised that inhibition of 11βHSD1 promotes physiological intra-retinal angiogenesis hence reducing ischaemia and the stimulus for pathological preretinal neovascularisation. Oxygen-induced retinopathy (OIR) was induced in newborn C57B6J mice by exposure to 75% oxygen from postnatal day 7 (P7) to day 12 (P12). Mice were treated daily from P12 to P17 with either an inhibitor of 11βHSD1 (Enamine compound 815; 30 mg/kg b.d.) or vehicle (5% cyclodextrin; 20 ml/kg) by intraperitoneal injection. The eyes were enucleated at P17 and the retinal microvasculature labelled with isolectin. Flat-mounted retinas were assessed for avascular, normovascular and neovascular areas (%). Data are mean±S.E.M., n=10–12. 11βHSD1 inhibition resulted in an increase in intra-retinal revascularisation (41.2±1.8 vs 27.5±1.7% in controls; P<0.00001) with a concomitant reduction in pathological neovascularisation (18.3±1.0 vs 29.1±1.7% in controls; P<0.00001). Residual retinal ischaemia at P17 was unchanged following 11βHSD1 inhibition (40.0±1.5 vs 43.4±1.6% in controls; P=0.20). These data suggest that pharmacological inhibition of 11βHSD1 improves angiogenic repair and reduces pathological neovascularisation during ischaemic retinopathy. 11βHSD1 inhibition may therefore be a therapeutic target in ischaemic retinopathies including retinopathy of prematurity and proliferative diabetic retinopathy.

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