Reduced Apoptosis and Increased Lesion Development in the Flow-Restricted Carotid Artery of p75-Null Mutant Mice

Apoptosis of neointimal smooth muscle cells is a well-recognized component of the pathogenesis of vascular lesions. In recent studies, we have identified the neurotrophin receptor, p75, as a mediator of apoptosis of neointimal smooth muscle cells. Neurotrophin ligands and p75 are selectively expressed in areas of atherosclerotic lesions with increased smooth muscle cell apoptosis and the neurotrophins are potent apoptotic agents for p75-expressing smooth muscle cells in vitro. In the present study, we directly assess the role of p75 in lesion development in the flow-restricted carotid artery, a model of murine vascular injury. Ligation of the left carotid artery resulted in a 3to 4-fold increase in lesion development in p75-null mutant mice as compared with wild-type mice. The increase in lesion size was associated with a 70% decrease in apoptosis of neointimal smooth muscle cells, as assessed by in situ TUNEL analysis. These data suggest that under conditions of flow restriction, p75 activation impairs lesion formation by promoting smooth muscle cell apoptosis. These results further implicate p75 as an important regulator of smooth muscle cell apoptosis and lesion development after vascular injury. (Circ Res. 2002;91:494-500.)