Latent Transforming Growth Factor-β Binding Protein-1, a Component of Latent Transforming Growth Factor-β Complex, Accelerates the Migration of Aortic Smooth Muscle Cells in Diabetic Rats Through Integrin-β3

Latent Transforming Growth Factor-β Binding Protein-1, a Component of Latent Transforming Growth Factor-β Complex, Accelerates the Migration of Aortic Smooth Muscle Cells in Diabetic Rats Through Integrin-β 3 Tetsuto Kanzaki and Masako Otabe From the Department of Internal Medicine, Kohnodai Hospital, National Center of Neurology and Psychiatry, Kohnodai, Ichikawa, Japan Abstract Aortic smooth muscle cells (SMCs) of diabetic animals have unique properties, including the overexpression of transforming growth factor-β (TGF-β) type II receptor, fibronectin, and platelet-derived growth factor β-receptor. TGF-β1 is produced and secreted as latent high–molecular weight complex consisting of mature TGF-β1, latency-associated peptide (LAP), and a latent TGF-β1 binding protein (LTBP-1). LAP has an important function in the latency of TGF-β complex, but the role of LTBP-1 is not known in diabetic angiopathy. SMC migration from the medial layer to the intimal layer of an artery is an initial major process of the formation of intimal thickening of an artery. Migration activities of SMCs from diabetic rat with 1–500 pg/ml of LTBP-1 increased significantly compared with that without LTBP-1. LTBP-1 at 10–500 pg/ml stimulated the migration of diabetic SMCs more than SMCs from control rat. An anti–integrin-β 3 antibody reduced LTBP-1–stimulated migration of diabetic SMCs to 51% compared with no antibody, but it did not reduce that of control SMCs. Furthermore, cross-linking experiments show that LTBP-1 binds integrin-β 3 in diabetic SMCs much more than in control SMCs in coincidence with the increase of integrin-β 3 in diabetic aorta by immunohistochemistry. Taken together, these observations suggest that LTBP-1 plays a critical role in intimal thickening of diabetic artery through the acceleration of SMC migration via integrin-β 3 . Footnotes Address correspondence and reprint requests to Tetsuto Kanzaki, Department of Internal Medicine, Kohnodai Hospital, National Center of Neurology and Psychiatry, 1-7-1, Kohnodai, Ichikawa City 272-8516, Japan. E-mail: kanzaki{at}intmed02.m.chiba-u.ac.jp . Received for publication 2 June 2002 and accepted in revised form 2 December 2002. 8-Cys, 8 cysteine; BCI, balloon catheter injury; DMEM, Dulbecco’s modified Eagles medium; EGF, epidermal growth factor; FBS, fetal bovine serum; LAP, latency-associated peptide; LTBP, latent TGF-β1 binding protein; PDGF, platelet-derived growth factor; RGD, arginine-glycine-aspartate; SMC, smooth muscl