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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2315.)
© 2005 American Heart Association, Inc.

Vascular Biology

Integrin _Vß₃ as a Target for Blocking HIV-1 Tat-Induced Endothelial Cell Activation In Vitro and Angiogenesis In Vivo

Chiara Urbinati; Stefania Mitola; Elena Tanghetti; Chandra Kumar; Johannes Waltenberger; Domenico Ribatti; Marco Presta; Marco Rusnati

From the Chair of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology (C.U., S.M., E.T., M.P., M.R.), University of Brescia, Italy; the Department of Tumor Biology (C.K.), Schering-Plough Research Institute, Kenilworth, New Jersey; the Department of Cardiology (J.W.), University Hospital Maastricht, The Netherlands; and the Institute of Human Anatomy, Histology, and Embryology (D.R.), University of Bari, Italy.

Correspondence to Marco Rusnati, General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, Viale Europa 11, 25123 Brescia, Italy. E-mail rusnati{at}med.unibs.it

Objective— The transactivating factor (Tat) of HIV-1 binds to _vß₃ integrin present on endothelial cells contributing to neovascularization. Here, we investigated the biological consequences of Tat/_vß₃ interaction and the antagonist effect of an Arg-Gly-Asp (RGD)-based peptidomimetic.

Methods and Results— Binding of Tat to endothelial _vß₃ triggers focal adhesion kinase and nuclear factor-B activation, leading to endothelial cell proliferation, membrane ruffling, and motility in vitro and neovascularization in vivo. The RGD-peptidomimetic SCH221153 inhibits Tat/_vß₃ interaction in a solid phase binding assay and endothelial cell adhesion to immobilized Tat with a potency higher than that of RGD-containing peptides. Accordingly, SCH221153 inhibits Tat/_vß₃-dependent focal adhesion kinase and nuclear factor-B activation, proliferation, membrane ruffling, and motility in endothelial cells. Finally, SCH221153 inhibits the angiogenic response triggered by Tat in the chick-embryo chorioallantoic membrane without affecting physiological vascularization. SCH221153 exerts these inhibitory effects without affecting the interaction of Tat with endothelial heparan sulfate proteoglycans or with the vascular endothelial growth factor receptor-2/kinase domain–containing receptor. In all the assays the negative control SCH216687 was ineffective.

Conclusion— These data provide new insights on the mechanism of endothelial cell activation by Tat and point to RGD peptidomimetics as prototypes for the development of novel Tat antagonists.

The transactivating factor (Tat) of HIV-1 binds to endothelial _vß₃ integrin triggering focal adhesion kinase and NF-B activation that lead to endothelial cell proliferation, membrane ruffling, and motility in vitro and neovascularization in vivo. The RGD-peptidomimetic SCH221153 inhibits these biological activities with high efficiency and specificity.

Key Words: HIV-1 • Tat • endothelium • integrin • angiogenesis