Model summary of integrins, ceramide, and apoptosis. Our data support a model in which inhibition of integrins (left) either activates ASMase, or removes inhibition from it, inducing generation of ceramide from sphingomyelin, activating caspases, and promoting apoptosis. ASMase may act downstream of integrins and/or function in a feedback loop to act on the integrins, possibly by altering lipid rafts, integrin clustering, integrin activation, and/or integrin signaling, and augment the signal, as in the case of CD95.⁵⁵  Molecular ordering of integrins, caspases, and ASMase is not known at this time. Under normal ligation of αvβ3/αvβ5 to matrix (right), ASMase is inactive (or suppressed), ceramide generation is at baseline, and apoptosis is inhibited, thus allowing endothelial cell survival. Traditional signaling pathways activated by integrin αvβ3/αvβ5 matrix ligation (eg, extracellular signal-related kinase [ERK], PI3K/Akt) are not depicted in this schema.