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The aggressive and malignant nature of AIDS-associated Kaposi's sarcoma (KS) lesions have largely been ascribed to Tat, the HIV-1 transactivator protein. Among other activities, HIV-Tat induces the migration and invasion of KS and endothelial cells. Since cell invasion is strictly correlated to the activity of lytic enzymes, we elucidated the role of the cell-associated plasminogen activation system in Tat-dependent and in constitutive invasion and proliferation of KS and of microvascular endothelial cells (MVEC). We demonstrate that KS cells and MVEC express the u-PA receptor (u-PAR) and release plasminogen activators and plasminogen activator inhibitor type-1 (PAI-1). The urokinase-type plasminogen activator (u-PA) is chemotactic, chemoinvasive and mitogenic for KS cells and for MVEC. Conditioned medium from KS cells induced invasion and proliferation of MVEC through the u-PA/u-PAR system. Tat is motogenic and mitogenic on KS cells and MVEC, and stimulates morphogenesis of MVEC. These activities were inhibited following antagonization of u-PA and u-PAR, which also reduced constitutive proliferation and invasion of KS cells and MVEC. These data indicate that the u-PA/u-PAR/PAI-1 system is involved in KS-induced endothelial cell invasion, proliferation, and differentiation. Further, exogenous Tat protein could up-regulate the fibrinolytic system, increasing its influence on KS and endothelial cell proliferation and migration, potentially promoting KS progression. These observations suggest the potential for application of u-PA/u-PAR system inhibitors for control of AIDS-associated KS, that has a high risk of recurrence with highly active antiretroviral therapy failure, and of other KS forms.

The HIV-Tat protein can be released extracellularly where it is able to recruit leukocytes and induce angiogenesis. These activities are mediated by the direct interaction of Tat with VEGFR2 on endothelial cells and chemokine receptors on leukocytes. We have recently shown that angiostatin, an anti-angiogenic peptide fragment of plasminogen, is able to inhibit the recruitment of neutrophils induced by bacterial fMLP and alpha chemokines both in vitro and in vivo. In vivo this was associated with an inhibition of the angiogenic response by angiostatin. These observations suggested that angiostatin could be a suitable inhibitor of Tat-induced angiogenesis, as it acts on both endothelial and neutrophil at the same time. In vitro, chemotaxis assays demonstrated that angiostatin inhibited Tat-induced chemotaxis of neutrophils with an inverse bell shaped profile. In vivo the injection of matrigel plugs containing Tat or its chemokine-like peptide (CysL24-51) caused the infiltration of neutrophils and a strong angiogenic response. Angiostatin completely blocked this inflammatory response, inhibiting the recruitment of inflammatory and endothelial cells inside the implant. Taken together, these results indicate that angiostatin can act as an inhibitor of both endothelial and neutrophil recruitment. As these cell types are also the targets of extracellularly released Tat, angiostatin could be used to contrast Tat-associated vasculopathies.