Although apoptosis of smooth muscle cells (SMCs) has been described as a prominent feature of vascular pathologies, its role in lesion development remains still unclear. Unlike necrosis, apoptosis is classically considered to be "silent," i.e., self-contained and non-inflammatory. The goal of my study was to develop a system that allows to initiate apoptosis of vascular SMCs in vivo, without exposing other cells to any pro-apoptotic stimuli. We have found that induction of apoptosis through tetracycline-regulated FADD overexpression in rat vascular SMCs in the carotid artery induces expression of MCP-1 and IL-8 and causes massive immigration of macrophages. A specific subset of proinflammatory genes, including MCP-1, IL-8 and IL-1a are also upregulated in human SMCs after treatment with Fas ligand (FasL) plus Cycloheximide (Chx). In the second part of my project, I am currently determining the mechanisms underlying this unusual response to apoptotic stimuli. I found that upregulation of MCP-1 expression occurs in two phases: a caspase-independent early phase (before 6 hrs) followed by a caspase-dependent late phase (24 hrs). The early MCP-1 upregulation is predominantly triggered by inhibition of protein synthesis, it also involves PIP3 activation and requires NF-kB signaling. The late induction of MCP-1 expression is mediated by the caspase-dependent release of IL-1a and does not occur in cells derived from caspase 8- or IL-1 receptor deficient mice. An important pathophysiological consequence of this second wave of activation could be that the secreted IL-1a acts on healthy neighboring cells to amplify the proinflammatory signal and prolong it beyond the time at which the original cell completed apoptosis.