Activation of matrix-metalloproteinase-2 and membrane-type-1-matrix-metalloproteinase in endothelial cells and induction of vascular permeability in vivo by human immunodeficiency virus-1 Tat protein and basic fibroblast growth factor

Previous studies indicated that the Tat protein of human immunodeficiency v irus type-1 (HIV-1) is a progression factor for Kaposi's sarcoma (KS). Spec ifically, extracellular Tat cooperates with basic fibroblast growth factor (bFGF) in promoting KS and endothelial cell growth and locomotion and in in ducing KS-like lesions in vivo. Here we show that Tat and bFGF combined inc rease matrix-metalloproteinase-2 (MMP-2) secretion and activation in endoth elial cells in an additive/synergistic manner. These effects are due to the activation of the membrane-type-1-matrix-metalloproteinase and to the indu ction of the membrane-bound tissue inhibitor of metalloproteinase-2 (TIMP-2 ) by Tat and bFGF combined, but also to Tat-mediated inhibition of both bas al or bFGF-induced TIMP-1 and -2 secretion. Consistent with this, Tat and b FGF promote vascular permeability and edema in vivo that are blocked by a s ynthetic MMP inhibitor. Finally, high MMP-2 expression is detected in acqui red immunodeficiency virus syndrome (AIDS)-KS lesions, and increased levels of MMP-2 are found in plasma from patients with AIDS-KS compared with HIV- uninfected individuals with classic KS, indicating that these mechanisms ar e operative in AIDS-KS. This suggests a novel pathway by which Tat can incr ease KS aggressiveness or induce vasculopathy in the setting of HIV-1 infec tion.