MODULATION OF BOVINE MICROVASCULAR ENDOTHELIAL-CELL PROTEOLYTIC PROPERTIES BY INHIBITORS OF ANGIOGENESIS

A tightly controlled increase in extracellular proteolysis, restricted both in time and space, is an important component of the angiogenic p rocess, while anti-proteolysis is effective in inhibiting angiogenesis . by focussing on the plasminogen activator (PA)-plasmin system, the o bjective of the present studies was to assess whether previously descr ibed inhibitors of angiogenesis modify bovine microvascular endothelia l cell proteolytic properties. We demonstrate that although synthetic angiostatic steroids (U-24067 and U-42129), heparin, suramin, interfer on alpha-2a, and retinoic acid are all inhibitors of in vitro angiogen esis, each of these agents has distinct effects on the plasminogen-dep endent proteolytic system. Specifically, angiostatic steroids and inte rferon alpha-2a reduce urokinase-type PA (u-PA) and PA inhibitor-1 act ivity, while heparin and retinoic acid increase u-PA activity. Suramin reduces cell-associated u-PA activity and greatly increases PAI-1 pro duction at doses which induce monolayer disruption. These findings dem onstrate that a spectrum of alterations in extracellular proteolysis i s associated with anti-angiogenesis, and that anti-angiogenesis and an ti-proteolysis are not necessarily correlated. A reduction in extracel lular proteolysis would be expected to reduce invasion, whereas an inc rease in proteolysis might modulate the activity of inhibitory cytokin es, which in turn could reduce endothelial cell proliferation and migr ation and inhibit angiogenesis. The spectrum of effects on different e lements of the PA system observed in response to the agents assessed s uggests that the role of modulations in extracellular proteolytic acti vity in anti-angiogenesis is likely to be varied and complex. (C) 1994 Wiley-Liss, Inc.