A possible mechanism for inhibition of angiogenesis by angiostatic steroids: induction of capillary basement membrane dissolution

Abstract

A new class of angiostatic steroids acts independently of previously identified steroid functions to inhibit angiogenesis when administered with heparin. Development of angiostatic steroids as therapeutic modulators of blood vessel growth would be greatly facilitated if their mode of action were thoroughly understood. However, the mechanism by which these steroids produce capillary regression is not known. The distributions of fibronectin and laminin were studied in growing and regressing capillaries by immunofluorescence microscopy to determine whether capillary basement membrane (BM) alterations could be involved in the mechanism of antiangiogenesis. In normal 8-day-old chick chorioallantoic membrane, fibronectin and laminin appeared in continuous linear patterns within BM surrounding growing capillaries. In contrast, chorioallantoic membranes treated with combinations of angiostatic steroid and heparin exhibited capillary BM fragmentation and eventually complete loss of fibronectin and laminin from regions of capillary involution. Capillary BM breakdown correlated with capillary retraction, endothelial cell rounding, and associated capillary regression. BM surrounding large vessels, neighboring epithelium, and nongrowing capillaries were not affected. Capillary BM dissolution is the first biochemical action identified for this new class of antiangiogenic steroids.