Integrin αvβ3 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

Research output: Contribution to journalArticlepeer-review

Abstract

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/αv3 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.

Original languageEnglish
Pages (from-to)2315-2320
Number of pages6
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume25
Issue number11
DOIs
Publication statusPublished - Nov 2005

Keywords

  • Angiogenesis
  • Endothelium
  • HIV-1
  • Integrin
  • Tat

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'Integrin αvβ3 as a target for blocking HIV-1 tat-induced endothelial cell activation in vitro and angiogenesis in vivo'. Together they form a unique fingerprint.

Cite this