It was hypothesised that generation of endogenous glucocorticoids by 11βHSD1 within the vessel wall regulates angiogenesis. <i>In vitro</i> mouse aortic ring cultures established that physiologically-relevant concentrations of glucocorticoids inhibit angiogenesis in a glucocorticoid receptor-dependent manner. In addition 11βHSD1 was found to modulate glucocorticoid-induced angiostasis, for 11dehydrocorticosterone (a substrate for 11βHSD1) although angiostatic in C57B16 aortae did not inhibit angiogenesis in llβHSD1 deficient animals. <i>In vivo</i> using subcutaneous sponge implants in mice, endogenous glucocorticoids were found to inhibit angiogenesis: sponges in adrenalectomised mice grew more vessels compared to sponges from sham-operated animals. 11βHSD1 regulated the angiostatic effects of glucocorticoids, for cortisone (the human equivalent of 11dehydrocorticosterone), although angiostatic in controls did not inhibit angiogenesis in 11βHSD1 deficient mice. <i>In pathology</i> in cutaneous wounds and infracted myocardium endogenous glucocorticoids were found to inhibit angiogenesis. RU38486, (a glucocorticoids receptor antagonist) in comparison to placebo enhanced angiogenesis in both tissues. In similar studies in C57B16 or llβHSD1 deficient mice, 11βHSD1 was found to tonically repress angiogenesis and impair left ventricular remodelling post infarction. Thus 11βHSD1 deficient mice had increased myocardial revascularisation and preserved left ventricular function. In conclusion, by using <i>in vitro</i>, <i>in vivo</i>, and <i>pathological </i>models, endogenous glucocorticoids were seen to inhibit angiogenesis. In addition, 11βHSD1 regeneration of glucocorticoids tonically repressed angiogenesis and influenced left ventricular remodelling post myocardial infarction. Thus 11βHSD1 appears to be an attractive therapeutic target for the management of tissue revascularisation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:662041 |
| Date | January 2005 |
| Creators | Small, Gary R. |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/29367 |
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