Integrins are αβheterodimeric cell surface adhesion receptors that mediate the physical interaction with the extracellular matrix and initiate signaling events necessary for cell adhesion, migration and positioning, and induce signaling event. The main signaling pathways activated by integrins include: MAPK, PI-3K-PKB/Akt, Rho family GTPases and Nuclear Factor-kB (NF-kB). Endothelial cell integrins are critical mediators and regulators of angiogenesis and vascular homeostasis. Extracellular integrin antagonists (i.e. small peptides or antibodies) suppress angiogenesis in many experimental models. In our laboratory we are exploring alternative approaches of suppressing angiogenesis by targeting integrin cytoplasmic domain and integrin-dependent intracellular signaling events. Expression of chimeric isolated β1 or β3 integrin subunit cytoplasmic domains, causes rapid disruption of focal adhesions and actin stress fibers, dissolution of VE-cadherin/β catenin localization at cell-cell contacts, cell rounding and detachment. In vitro, HUVEC expressing isolated β1 integrin subunit cytoplasmic domain detached in the absence of detectable cleavage of caspase-8, -3, and PARP, suppression of FAK, ERK, PKB and Ik-B phosphorylation, and significant increased in cell death up to 24 hours after construct expression. In vivo expression of isolated b integrin in endothelial cells of quiescent vessels caused acute endothelial cell rounding and detachment followed by an increase in DNA-fragmentation in the detached cells. These results demonstrate that cell detachment induced by expressed isolated β1 cytoplasmic domain preceded cell death and revealed an essential role of integrins for the adhesion and survival of quiescent arterial endothelial cells in vivo. Inhibition of endothelial cell COX-2 by non steroidal anti-inflammatory drugs suppress αVβ3 -dependent Rac activation, endothelial cell spreading, migration in vitro and FGF-2-induced angiogenesis in vivo. The COX-2 metabolite PGE2 accelerated aVβ3-mediated HUVEC adhesion and promoted Rac activation and cell spreading. αVβ3-mediated adhesion induced a transient COX-2-dependent rise in cAMP levels, while the cell permeable cAMP analogue 8-brcAMP accelerated adhesion, promoted Rac activation and cell spreading. We have recently shown that integrin-mediated cell adhesion and soluble integrin ligands contribute to maintaining COX-2 steady-state levels in endothelial cells by the combined prevention of lysosomal-dependent degradation and the stimulation of mRNA synthesis involving multiple signaling pathways.