The angiogenesis induced by HIV–1 Tat protein is mediated by the Flk–1/KDR receptor on vascular endothelial cells

Abstract

The HIV-1 Tat protein transactivates HIV, viral and some host cell genes. Tat can be released by infected cells and acts extracellularly in the microenvironment, regulating functions of immunocompetent and mesenchymal cells. One of the most striking effects of Tat is the induction of a functional program in vascular cells related to angiogenesis and inflammation (migration, proliferation and expression of plasminogen activator inhibitor-1 and E selectin). Tat induces growth of Kaposi's sarcoma (KS) spindle cells and is angiogenic in vivo and in transgenic mice10-12. We previously reported that Tat is a direct angiogenic factor and noted the Tat arginine- and lysine-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 specifically binds and activates the Flk-1/kinase insert domain receptor (Flk-1/KDR), a VEGF-A tyrosine kinase receptor (for review see ref. 13), and that Tat-induced angiogenesis is blocked by agents blocking the Flk-1/KDR receptor. Endothelial cell stimulation by Tat occurs in the absence of activation of FLT-1, another VEGF-A tyrosine kinase receptor.

Peptide blockade of HIFα degradation modulates cellular metabolism and angiogenesis

“…Further experiments on day 7 (Fig. 5b) showed activity of tat-CODD compared to tat-CODD mut excluding a contribution from the tat component (27). The vessel endothelium within sponges was surrounded by cells expressing smooth muscle actin (results not shown), compatible with the generation of more mature and less leaky vessels than those generated by individual growth factors (28)(29)(30)(31).…”

The Human Immunodeficiency Virus-1 Tat Protein Activates Human Umbilical Vein Endothelial Cell E-selectin Expression via an NF-κB-dependent Mechanism

“…On the other hand, even without transfection, Tat is able to enter cells, since its positively charged protein transduction domain stimulates cellular uptake (59,60) and its RGD domain is responsible for binding to cell surface integrins (10). The RGD and basic domains of Tat stimulate and modulate the VEGF receptor Flk-1/KDR and components of the focal adhesion kinase in Kaposi's sarcoma cells (61,62).…”

Physical and Functional Interaction of HIV-1 Tat with E2F-4, a Transcriptional Regulator of Mammalian Cell Cycle

“…Moreover, Tat binds to cyclin T and recruits CDK9 to increase the processivity of RNA polymerase II (12, 30 -32). The second exon of tat codes for the C terminus of the protein and appears to mediate a large array of cellular activities by interacting with several cell surface receptors including integrin receptors (33), vascular endothelial growth factor, and chemokine receptors (34,35). Tat protein may be directly involved in the development of some AIDSrelated diseases by interfering with cellular processes such as proliferation, differentiation, and apoptosis (36).…”