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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:370.)
© 2000 American Heart Association, Inc.

Vascular Biology

Insulin-Like Growth Factor Binding Protein-4 Expression Is Decreased by Angiotensin II and Thrombin in Rat Aortic Vascular Smooth Muscle Cells

A. Anwar; A. A. Zahid; L. Phillips; P. Delafontaine

From the Hôpital Cantonal Universitaire de Genève, Geneva, Switzerland, and Emory University (L.P.), Division of Cardiology, Atlanta, Ga.

Correspondence to Dr Asif Anwar, Centre de Cardiologie, Hôpital Cantonal Universitaire de Genève, Rue Micheli du Crest 24, 1211 Genève-14, Switzerland. E-mail Asif.Anwar{at}hcuge.ch

Abstract—Insulin-like growth factor-I (IGF-I) is a ubiquitous peptide that regulates cellular growth and differentiation and is involved in vascular proliferative responses. The effects of IGF-I are modulated by several IGF-I binding proteins (IGFBPs), including IGFBP-4, the main IGFBP produced by vascular smooth muscle cells (VSMCs). We have previously shown that angiotensin II (Ang II)–induced and thrombin-induced mitogenesis in VSMCs is dependent on autocrine IGF-I. In addition, we have demonstrated that IGF-I and IGFBP-4 mRNA levels are upregulated in the hypertensive aorta of abdominally coarcted rats, a high-renin hypertension model. To obtain further insight into the IGF-I system and to specifically study changes in IGFBP-4, a known inhibitor of IGF-I action, VSMCs were incubated with Ang II or thrombin. Compared with control, Ang II induced an 87±2% downregulation of IGFBP-4 mRNA levels at 24 hours, with a 61±6% decrease of IGFBP-4 levels, as determined by Western ligand blot analysis. Thrombin had the same depressor effects (87±2% for the mRNA levels and 61±3% for the protein levels). Ang II and thrombin coincubation with ¹²⁵I-IGFBP-4 in the conditioned media failed to reveal any increase in fragmentation, indicating that proteolytic cleavage of IGFBP-4 was not involved in the observed effects. Exogenous recombinant human IGFBP-4 decreased thrombin-induced DNA synthesis of human aortic VSMCs by 64%, whereas anti–IGFBP-4 antibody potentiated thrombin-induced DNA synthesis. These data suggest that downregulation of IGFBP-4 expression in VSMCs may play a critical role in vascular growth response to Ang II and thrombin in normal and diseased states, by increasing the bioavailability of IGF-I for its cell-surface receptor.

Key Words: insulin-like growth factor binding proteins • gene expression • vascular smooth muscle cells • angiotensin II • thrombin

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