Mechanisms underlying corticosterone mediated inhibition of angiogenesis

Abstract

Angiogenesis involves cell proliferation, invasion and migration of endothelial cells. Corticosterone (CORT), elevated in diabetes and metabolic syndrome, is known to be angiostatic, but it's mechanisms of action are unknown. Previously, we found that CORT inhibits matrix metalloproteinase (MMP)‐2 production and activity. We treated rat microvascular endothelial cells with 600 nM CORT for 48 hrs and found a significant decrease in full length MMP‐2 promoter activity using a luciferase reporter assay. This effect was localized to a region between ‐1560 and ‐1386 bp. However, pretreatment of cells with 10 μM RU 486 (glucocorticoid receptor (GR) antagonist) for 2 hrs did not block the CORT mediated inhibition of MMP‐2 production or activation. To observe the effect of CORT on endothelial cell sprouting, we cultured cell spheroids in type‐1 collagen and treated them with CORT for 48 hrs. At 24 hrs CORT treated cells displayed numerous sprouts, similar to controls, but at 48 hrs, sprouts had destabilized and regressed in response to CORT. Our data suggest that the mechanism of CORT‐dependent inhibition of MMP‐2 production may be due to reduced transcription, but that this may not be GR‐mediated. In future studies, we will identify intracellular signals affected by CORT treatment that may contribute to sprout repression. Funding by NSERC & HSFO.Grant Funding SourceNSERC