Inhibition or deletion of 11Β-HSD1 does not increase angiogenesis in ischemic retinopathy

11-Hydroxysteroid dehydrogenase type I (11-HSD1) regenerates active glucocorticoids (cortisol in humans, corticosterone in rodents) from inert 11-keto metabolites [1]. Selective 11-HSD1 inhibitors have been shown to be safe and effective in the treatment of type 2 diabetes [2], lowering intracellular glucocorticoid concentrations in liver and adipose tissue (and thereby enhancing insulin sensitivity) [3]. They also improve a number of features of the metabolic syndrome, including liver fat content [4], are potentially atheroprotective [5] and improve cognition [6]. Although no longer under development for blood glucose lowering alone, 11-HSD1 inhibitors are being re-profiled for additional indications and may yet be prescribed in patients with type 2 diabetes.
11-HSD1 is also expressed in smooth muscle cells throughout the vasculature [7]. By acting directly through glucocorticoid receptors in the blood vessel wall, glucocorticoids tonically inhibit angiogenesis [8]. Loss of 11-HSD1, and the resulting reduction of glucocorticoid action in blood vessels, is associated with enhanced angiogenesis in multiple sites and has been shown to be beneficial in the myocardium after coronary artery occlusion and in skin following wound incision [9].
Angiogenesis can also contribute to pathology, as seen in solid tumour development and ischemic retinopathies such as retinal vein occlusions and proliferative diabetic retinopathy (PDR). If 11-HSD1 inhibitors are to be used for chronic treatment in patients with type II diabetes, then there is a concern that they may accelerate the progression of inappropriate blood vessel growth in the retina and exacerbate progression to sight-threatening PDR.
This study tests the hypothesis that pharmacological inhibition or deletion of 11-HSD1 promotes pathological retinal neovascularisation. Retinal vascular remodelling was induced using the oxygen induced retinopathy (OIR) model [10] in which exposure of neonatal mice to hyperoxia from postnatal days 7 to 12 causes obliteration and cessation of development of central retinal capillary beds so that, on return to normoxia, a potent pre-retinal neovascular response is induced. Expression and localisation of 11β-HSD1 in the retina was also investigated by immunohistochemistry.