THE ANGIOGENESIS INDUCED BY HIV-1 TAT PROTEIN IS MEDIATED BY THE FLK-1 KDR RECEPTOR ON VASCULAR ENDOTHELIAL-CELLS/

The HIV-1 Tat protein transactivates HIV, viral and some host cell gen es(1). Tat can be released by infected cells(2) and acts extracellular ly in the microenvironment, regulating functions of immunocompetent an d mesenchymal cells(3,4). One of the most striking effects of Tat is t he induction of a functional program in vascular cells related to angi ogenesis and inflammation (migration, proliferation and expression of plasminogen activator inhibitor-1 and E selectin(5-7)). Tat induces gr owth of Kaposi's sarcoma (KS) spindle cells(8) and is angiogenic in vi vo(7,9) and in transgenic mice(10-12). We previously reported that Tat is a direct angiogenic factor(7) and noted the Tat arginine- and lysi ne-rich sequence is similar to that of other potent angiogenic growth factors, such as vascular endothelial growth factor-A (VEGF-A). It is possible that Tat mimics one of these factors by interacting with its growth factor tyrosine kinase receptor. Here we demonstrate that Tat s pecifically binds and activates the Flk-1/kinase insert domain recepto r (Flk-1/KDR), a VEGF-A tyrosine kinase receptor (for review see ref. 13), and that Tat-induced angiogenesis is blocked by agents blocking t he Flk-1/KDR receptor. Endothelial cell stimulation by Tat occurs in t he absence of activation of FLT-1, another VEGF-A tyrosine kinase rece ptor.