Angiogenesis is the creation of new blood vessels from the existing vasculature that
occurs through a complex series of interactions and is tightly regulated.
Glucocorticoids are acknowledged to inhibit angiogenesis at high concentrations but
whether endogenous glucocorticoid concentrations are sufficient to regulate
angiogenesis is unclear. Adrenal synthesis is not the sole determinant of
glucocorticoid tissue concentration however and 11 ßhydroxysteroid dehydrogenase
type 1 (11ßHSD1) that is present in the vessel wall may regenerate active
glucocorticoids from 1 lketo-substrates and therefore amplify local tissue
concentrations. Thus it was hypothesised that endogenous glucocorticoids regulated
by 11ßHSD1 inhibit angiogenesis.
In vitro C57B16 mouse aortic ring cultures established that physiologically relevant
concentrations of glucocorticoids inhibit angiogenesis in a glucocorticoid receptor
dependent manner. In addition vascular 11ßHSD1 was found to modulate
glucocorticoid-induced angiostasis, for 1 ldehydrocorticosterone although angiostatic
in C57B16 aortae did not inhibit angiogenesis in 11ßHSD1 deficient animals.
In vivo using polyester sponge subcutaneous implants in mice, endogenous
glucocorticoids were found to inhibit angiogenesis: sponges in adrenalectomised
C57B16 mice grew more vessels compared to sponges from sham-operated animals.
11ßHSD1 regulated the angiostatic effects of glucocorticoids, for cortisone (the
human equivalent of 11dehydrocorticosterone), although angiostatic in wild types
did not inhibit angiogenesis in 11ßHSD1 deficient mice. In vivo it was also noted
that in placebo-impregnated sponges angiogenesis was greater in 11ßHSD1 deficient
compared to C57B16 mice.
In pathology in cutaneous wounds and infarcted myocardium, endogenous
glucocorticoids were found to inhibit angiogenesis. RU38486 (a glucocorticoid
receptor antagonist) enhanced angiogenesis in both tissues in comparison to placebo
treatment. In similar studies in C57B16 or 11ßHSD1 deficient mice, 11ßHSD1 was
found to tonically repress angiogenesis and impair left ventricular remodelling post
infarction. Thus 11ßHSD1 deficient mice had increased myocardial revascularisation
and preserved left ventricular function.
In conclusion, by using in vitro, in vivo and pathological models, endogenous
glucocorticoids were seen to inhibit angiogenesis. In addition 11ßHSD1 regeneration
of glucocorticoids tonically repressed angiogenesis and influenced left ventricular
remodelling post myocardial infarction. Thus 11ßHSD1 appears to be an attractive
therapeutic target for the management of tissue revascularisation.