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Experimental Diabetes Research
Volume 2010, Article ID 617052, 12 pages
http://dx.doi.org/10.1155/2010/617052
Research Article

Glucose Regulation of Thrombospondin and Its Role in the Modulation of Smooth Muscle Cell Proliferation

Division of Endocrinology, University of North Carolina, CB# 7170, 5030 Burnett Womack, Chapel Hill, NC 27599-7170, USA

Received 1 February 2010; Revised 5 April 2010; Accepted 16 April 2010

Academic Editor: Toshiyasu Sasaoka

Copyright © 2010 Laura A. Maile et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Smooth muscle cells (SMC) maintained in high glucose are more responsive to IGF-I than those in normal glucose. There is significantly more thrombospondin-1 (TSP-1) in extracellular matrix surrounding SMC grown in 25 mM glucose. In this study we investigated 1) the mechanism by which glucose regulates TSP-1 levels and 2) the mechanism by which TS-1 enhances IGF-I signaling. The addition of TSP-1 to primary SMC was sufficient to enhance IGF-I responsiveness in normal glucose. Reducing TSP-1 protein levels inhibited IGF-I signaling in SMC maintained in high glucose. We determined that TSP-1 protected IAP/CD47 from cleavage and thereby facilitated its association with SHP substrate-1 (SHPS-1). We have shown previously that the hyperglycemia induced protection of IAP from cleavage is an important component of the ability of hyperglycemia to enhance IGF-I signaling. Furthermore we determined that TSP-1 also enhanced phosphorylation of the 3 subunit of the V 3 integrin, another molecular event that we have shown are critical for SMC response to IGF-I in high glucose. Our studies also revealed that the difference in the amount of TSP-1 in the two different glucose conditions was due, at least in part, to a difference in the cellular uptake and degradation of TSP-1.