VeGFr2/avb3–integrin Complex Formation and Polarization in endothelial Cells

Angiogenesis plays a key role in various physiological and pathological conditions, including embryonic development, wound repair, inflammation, and tumor growth. The uncontrolled release of angiogenic growth factors (AGFs) is responsible for the endothelial cell (EC) proliferation that takes place during tumor neovascularization and angiogenesisdependent diseases. Numerous inducers of angiogenesis, including members of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) families are produced by tumor or inflammatory cells, accumulate in extracellular matrix (ECM) and eventually interact with tyrosine kinase receptors (TKRs) expressed on EC surface. TKR activity is modulated by integrin receptors that regulate EC response to AGFs by binding various cell adhesive ECM proteins, including collagens (CO), vitronectin (VN), fibronectin (FN), and fibrin(ogen) (FG). Thus, the angiogenic process, far from being the mere outcome of an apparently straightforward AGF/TKR interaction, is regulated in a complex fashion by distinct sets of inputs conveyed to ECs by free AGFs interacting with TKRs at the luminal aspect of ECs and by cell adhesive proteins interacting with integrins at the basal aspect of ECs. The HIV-1 transactivating factor (Tat) is a cationic polypeptide released by HIVinfected cells that, in its extracellular form, induces several pathological effects by targeting HIVuninfected cells. In particular, extracellular Tat induces neovascularization by targeting ECs, contributing to the arise of angiogenesisrelated diseases (including Kaposi sarcoma and retinal microangiopathy), frequently observed in AIDS patients. Tat may represent a powerful tool to study the complex mechanisms of neovascularization. Indeed, it shares important features with both AGFs and cell adhesive proteins. Similar to VEGF, Tat binds the TKVEGF receptor-2 Flk-1/ KDR (VEGFR2), inducing ERK 1/2 phosphorylation and EC proangiogenic activation. At the same time, like a typical cell adhesive protein, Tat accumulates in ECM, binds a v  3 integrin receptors, promotes EC adhesion and triggers the FAK/RhoA/NF-kB pathway required for the proangiogenic response. Intriguingly, as demonstrated for VEGF, a v  3 and VEGFR2 couple in ECs on Tat engagement. substrateimmobilized HiV-1 tat drives VeGFr2/avb3–integrin Complex Formation and Polarization in endothelial Cells