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

Abstract EN

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 β3 subunit of the αVβ3 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.