TY - JOUR
T1 - Integrin αvβ3 as a target for blocking HIV-1 tat-induced endothelial cell activation in vitro and angiogenesis in vivo
AU - Urbinati, Chiara
AU - Mitola, Stefania
AU - Tanghetti, Elena
AU - Kumar, Chandra
AU - Waltenberger, Johannes
AU - Ribatti, Domenico
AU - Presta, Marco
AU - Rusnati, Marco
PY - 2005/11
Y1 - 2005/11
N2 - Objective - The transactivating factor (Tat) of HIV-1 binds to αvβ3 integrin present on endothelial cells contributing to neovascularization. Here, we investigated the biological consequences of Tat/αv/β3 interaction and the antagonist effect of an Arg-Gly-Asp (RGD)-based peptidomimetic. Methods and Results - Binding of Tat to endothelial αvβ3 triggers focal adhesion kinase and nuclear factor-κB activation, leading to endothelial cell proliferation, membrane ruffling, and motility in vitro and neovascularization in vivo. The RGD-peptidomimetic SCH221153 inhibits Tat/αvβ3 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/αvβ3-dependent focal adhesion kinase and nuclear factor-κB 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.
AB - Objective - The transactivating factor (Tat) of HIV-1 binds to αvβ3 integrin present on endothelial cells contributing to neovascularization. Here, we investigated the biological consequences of Tat/αv/β3 interaction and the antagonist effect of an Arg-Gly-Asp (RGD)-based peptidomimetic. Methods and Results - Binding of Tat to endothelial αvβ3 triggers focal adhesion kinase and nuclear factor-κB activation, leading to endothelial cell proliferation, membrane ruffling, and motility in vitro and neovascularization in vivo. The RGD-peptidomimetic SCH221153 inhibits Tat/αvβ3 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/αvβ3-dependent focal adhesion kinase and nuclear factor-κB 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.
KW - Angiogenesis
KW - Endothelium
KW - HIV-1
KW - Integrin
KW - Tat
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U2 - 10.1161/01.ATV.0000186182.14908.7b
DO - 10.1161/01.ATV.0000186182.14908.7b
M3 - Article
C2 - 16166568
AN - SCOPUS:27644440286
VL - 25
SP - 2315
EP - 2320
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 11
ER -