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Am J Physiol Heart Circ Physiol 279: H2159-H2165, 2000;
0363-6135/00 $5.00
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Vol. 279, Issue 5, H2159-H2165, November 2000

Autocrine thrombospondin partially mediates TGF-beta 1- induced proliferation of vascular smooth muscle cells

Mansoor Sajid, Manjiri Lele, and George A. Stouffer

Sealy Center for Molecular Cardiology, University of Texas Medical Branch, Galveston, Texas 77555

Transforming growth factor (TGF)-beta 1 has been implicated in vascular healing responses after mechanical injury. Using cultured rat aortic smooth muscle cells (RASMC), we examined the hypothesis that production and secretion of thrombospondin (TSP) contributes to TGF-beta 1-induced proliferation. We found that TGF-beta 1 enhanced production and secretion of TSP, with peak levels of secreted TSP observed 24 h after treatment. RASMC treated with TGF-beta 1 secreted a mitogenic activity that was transferable in conditioned media and partially inhibited by C6.7, a monoclonal anti-TSP antibody. Exogenous TSP stimulated a proliferative response, with maximal [3H]thymidine incorporation occurring 24 h earlier than maximal [3H]thymidine incorporation in response to TGF-beta 1-treatment. Pretreatment with C6.7 or polyclonal anti-TSP neutralizing antibodies inhibited TGF-beta 1-induced proliferation of RASMC. Proliferative responses to TGF-beta 1 were also inhibited by pretreatment with an anti-beta 3 integrin monoclonal blocking antibody (F11), RGD peptides, and the anti-alpha vbeta 3 disintegrin echistatin. Treatment with TSP and TGF-beta 1 increased c-Jun NH2-terminal kinase (JNK)1 activity, with peak effects observed at 15 min and 4 h, respectively. Treatment with C6.7 or F11 inhibited TGF-beta -induced activation of JNK1. In summary, these studies support the hypothesis that TGF-beta -induced JNK1 activation and proliferation of RASMC require secretion of TSP and ligation of alpha vbeta 3-integrins.

transforming growth factor; receptors; vitronectin; extracellular matrix; angioplasty


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