Abstract
The process of angiogenesis is important in both normal and pathologic physiology. However, the mechanisms whereby factors such as basic fibroblast growth factor promote the formation of new blood vessels are not known. In the present study, we demonstrate that exogenously added plasminogen activator inhibitor-1 (PAI-1) at therapeutic concentrations is a potent inhibitor of basic fibroblast growth factor-induced angiogenesis in the chicken chorioallantoic membrane. By using specific PAI-1 mutants with either their vitronectin binding or proteinase inhibitor activities ablated, we show that the inhibition of angiogenesis appears to occur via two distinct but apparently overlapping pathways. The first is dependent on PAI-1 inhibition of proteinase activity, most likely chicken plasmin, while the second is independent of PAI-1's anti-proteinase activity and instead appears to act through PAI-1 binding to vitronectin. Together, these data suggest that PAI-1 may be an important factor regulating angiogenesis in vivo.
Highlights
PAI-11 is the primary inhibitor of urokinase-type plasminogen activator and tissue-type plasminogen activator [1, 2]
We demonstrate that exogenously added plasminogen activator inhibitor-1 (PAI-1) at therapeutic concentrations is a potent inhibitor of basic fibroblast growth factor-induced angiogenesis in the chicken chorioallantoic membrane
PAI-1 Blocks Angiogenesis in the Chick CAM—Previously, we demonstrated that vitronectin enhanced the migration of smooth muscle cells in vitro and that PAI-1 was an efficient inhibitor of this enhancement [10]
Summary
PAI-11 is the primary inhibitor of urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator [1, 2]. These demonstrated that the constitutively active form of PAI-1 (14-1b) used in our studies did not bind to MA33B8 coated onto microtiter plates prior to complex formation with chicken plasmin when detected with rabbit anti-human PAI-1 antiserum (data not shown).
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