Preventing local regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 enhances angiogenesis

Abstract

Angiogenesis restores blood flow to healing tissues, a process that is inhibited by high doses of glucocorticoids. However, the role of endogenous glucocorticoids and the potential for antiglucocorticoid therapy to enhance angiogenesis is unknown. Using in vitro and in vivo models of angiogenesis in mice, we examined effects of (i) endogenous glucocorticoids, (ii) blocking endogenous glucocorticoid action with the glucocorticoid receptor antagonist RU38486, and (iii) abolishing local regeneration of glucocorticoids by the enzyme 11␤-hydroxysteroid dehydrogenase type 1 (11␤HSD1). Glucocorticoids, administered at physiological concentrations, inhibited angiogenesis in an in vitro aortic ring model and in vivo in polyurethane sponges implanted s.c. RU38486-enhanced angiogenesis in s.c. sponges, in healing surgical wounds, and in the myocardium of mice 7 days after myocardial infarction induced by coronary artery ligation. 11␤HSD1 knockout mice showed enhanced angiogenesis in vitro and in vivo within sponges, wounds, and infarcted myocardium. Endogenous glucocorticoids, including those generated locally by 11␤HSD1, exert tonic inhibition of angiogenesis. Inhibition of 11␤HSD1 in liver and adipose has been advocated to reduce cardiovascular risk in the metabolic syndrome: these data suggest that 11␤HSD1 inhibition offers a previously uncharacterized therapeutic approach to improve healing of ischemic or injured tissue. myocardial infarction ͉ wound healing

Enhanced Hippocampal Long-Term Potentiation and Spatial Learning in Aged 11β-Hydroxysteroid Dehydrogenase Type 1 Knock-Out Mice

“…In addition, any inflammation would be anticipated to impair memory with age (Teunissen et al, 2003;Dik et al, 2005), but this was not seen. Similarly, 11␤-HSD1 is expressed in the vasculature and 11␤-HSD1 Ϫ/Ϫ mice exhibit increased angiogenesis, at least in myocardial ischemia (Small et al, 2005). Angiogenesis supports neoplasia and metastasis, but there was no evidence of excess of these pathologies with aging in 11␤-HSD1 Ϫ/Ϫ mice.…”

Glucocorticoids and Cardiovascular Disease

“…While loss of 11b-HSD2 dehydrogenase inactivation of glucocorticoid in the endothelium was associated with enhanced vasoconstrictor responses, loss of 11b-HSD1 reductase regeneration of glucocorticoid in vascular smooth muscle did not influence vascular tone. More recent studies suggest that 11b-HSD1 influences remodelling responses in the vasculature (see below (63,86)). In vascular cells and macrophages in vitro, pro-inflammatory cytokines up-regulate 11b-HSD1 expression (76,77,87), raising the intriguing possibility that local amplification of cortisol concentrations provides a counter-regulatory response which modifies remodelling during vascular injury or inflammation.…”

“…1A) and influences fibrotic responses (133). In addition, GR activation prevents angiogenesis (86,134,135), a key process in the recovery from infarction which ensures collateral circulation and reperfusion. Administration of glucocorticoids beyond the first few days after infarction might be predicted to impair reperfusion.…”

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

“…mice show increased angiogenic responses, which contributes to their improved recovery after myocardial infarction in vivo (Small et al, 2005). Angiogenesis is a key determinant of adipose tissue expansion during obesity and inhibition of this process prevents obesity (Rupnick et al, 2002, Lijnen et al, 2008.…”