Impact of apolipoprotein(a) on in vitro angiogenesis

Angiostatin, which consists of the kringle I-IV domains of plasminogen and which is secreted into urine, is an efficient inhibitor of angiogenesis and tumor growth. Because N-terminal apolipoprotein(a) [apo(a)] fragments, whi ch also contain several types of kringle IV domains, are found in urine as well, we evaluated the potential angiostatic properties of these urinary ap o(a) fragments and of a recombinant form of apo(a) [r-apo(a)]. We used huma n microvascular endothelial cell (hMVEC)-based in vitro assays of tube form ation in 3-dimensional fibrin matrixes Purified urinary apo(a) fragments or r-apo(a) inhibited the basic fibroblast growth factor/tumor necrosis facto r-alpha -induced formation of capillary-like structures. At concentrations varying from 0.2 to 10 mug/mL, urinary apo(a) fragments inhibited tube form ation by as much as 70%, whereas there was complete inhibition by r-apo(a). The highest concentrations of both inhibitors also reduced urokinase plasm inogen activator production of basic fibroblast growth factor-induced hMVEC proliferation. The inhibitors had no effect on plasminogen activator inhib itor-1 expression. If our in vitro model for angiogenesis is valid for the in vivo situation as well, our data point toward the possibility that apo(a ) may also be physiologically operative in modulating angiogenesis, as the concentration of free apo(a) found in humans exceeds that tested herein.