NGF exhibits a pro-apoptotic activity for human vascular smooth muscle cells that is inhibited by TGF beta 1

Apoptosis of vascular smooth muscle cells (SMCs) has been described in culture and also during remodelling of the artery following injury, However, the mediators that regulate apoptosis in SMCs are unknown, Because neurotrophins, a family of related polypeptide growth factors, including nerve growth factor (NGF) and its cognate receptor TrkA have been shown to be strongly expressed in atherosclerotic lesions, the present study was undertaken to evaluate in vitro, the activity of NGF with regard to apoptosis of confluent cultures of human aortic SMCs, We report here that NGF induced apoptosis of SMCs in a dose-dependent manner, This effect,vas detected from the concentration of 1 ng/ml and reached a maximum at 100 ng/ml, The concentration that induced a half-maximum effect was 8.8 ng/ml, The pro-apoptotic activity of NGF was time dependent and was significant after 3 h of incubation, The proapoptotic activity of NGF was blocked in a dose-dependent manner by K-252a, an inhibitor of TrkA tyrosine phosphorylation, suggesting that a NGF/TrkA signal transduction pathway could activate apoptotic cell death programs in human SMCs, Significantly, NGF-induced apoptosis was inhibited by wortmannin and PD 98059, showing that both PI3 kinase and MEK kinase were involved, At a NGF concentration that strongly induced apoptosis (100 ng/ml), TGF beta 1 which has been identified several times as a protective factor, dose dependently inhibited the pro-apoptotic effect of NGF, The IC50 value was 1.5 ng/ml, These results indicate that, at least in vitro, TGF beta 1 can inhibit the pro-apoptotic activity of NGF for SMCs therefore suggesting that TGF beta 1 has the capacity to diminish the deleterious consequences of an excitotoxic or ischemic injury that might occur during atherogenesis or following angioplasty. (C) 1997 Federation of European Biochemical Societies.