The programmed form of cell death (apoptosis) is essential for normal development of multicellular organisms. Dysregulation of apoptosis has been linked with embryonal death and is involved in the pathophysiology of various diseases. Specifically, endothelial apoptosis plays pivotal roles in atherosclerosis whereas prevention of endothelial apoptosis is a prerequisite for neovascularization in tumors and metastasis. Endothelial biology is intertwined with the composition of subendothelial basement membrane proteins. Apoptosis was induced by addition of tumor necrosis factorto cycloheximide-sensitized endothelial cells. Cells were either grown on polystyrene culture plates or on plates precoated with healthy basement membrane proteins (collagen IV, fibronectin, or laminin) or collagen I. Our results reveal that proteins of healthy basement membrane alleviate cytokine-induced apoptosis whereas precoating with collagen type I had no significant effect on apoptosis by addition of tumor necrosis factorto cycloheximide-sensitized endothelial cells compared with cells cultured on uncoated plates. Yet, treatment with transforming growth factor-1 significantly reduced the rate of apoptosis endothelial cells grown on collagen I. Detailed analysis reveals differences in intracellular signaling pathways for each of the basement membrane proteins studied. We provide additional insights into the importance of basement membrane proteins and the respective cytokine milieu on endothelial biology. Exploring outside-in signaling by basement membrane proteins may constitute an interesting target to restore vascular function and prevent complications in the atherosclerotic cascade.