IGF I is an ubiquitous peptide that activates a membrane tyrosine kinase receptor and has autocrine/paracrine effects on vascular smooth muscle cells. Thrombin activates a G-protein coupled receptor and is also a mitogen for vascular smooth muscle cells. To assess the potential role of IGF I as a mediator of thrombin's effects, we characterized expression of IGF I and of its receptor on vascular smooth muscle cells exposed to thrombin. Thrombin dose-dependently decreased IGF I mRNA levels and caused a delayed decrease in IGF I secretion from vascular smooth muscle cells. This effect was mimicked by the hexapeptide SF-FLRN (that functions as a tethered ligand) and was inhibited by hirudin. In contrast, thrombin doubled IGF I receptor density on vascular smooth muscle cells, without altering binding affinity (Kd). An anti-IGF I antiserum markedly reduced thrombin-induced DNA synthesis, whereas nonimmune serum and an anti-fibroblast growth factor antibody were without effect. Cell counts confirmed these results. Downregulation of IGF I receptors by antisense phosphorothioate oligonucleotides likewise markedly inhibited thrombin-induced DNA synthesis. These data demonstrate that a functional IGF I-IGF I receptor pathway is essential for thrombin-induced mitogenic signaling and support the concept of cross talk between G-protein coupled and tyrosine kinase receptors.
P Delafontaine, A Anwar, H Lou, L Ku
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