Thrombospondin-1-induced vascular smooth muscle cell migration is dependent on the hyaluronic acid receptor CD44

Thrombospondin-1 (TSP-1) induces vascular smooth muscle cell (VSMC) migration after arterial injury. TSP-1 up-regulates hyaluronic acid (HyA)-inducing genes in VSMCs. HyA also induces VSMC migration. Our hypothesis was that TSP-1-induced VSMC migration is dependent on the CD44 receptor, and that HyA and TSP-1 share migratory signaling pathways.

VSMC migration was assessed using TSP-1, HyA, or serum-free medium as chemoattractants. VSMCs were treated with inhibitors to CD44, Ras, phosphatidylinositol-3 kinase, Raf-1 kinase, or c-SRC. TSP-1- and HyA-induced epidermal growth factor receptor (EGFR) activity was determined by enzyme-linked immunosorbent assay. Comparisons were made by the Student t test and a P value less than .05 was considered significant.

Inhibiting CD44 reduced TSP-1- and HyA-induced migration. Phosphatidylinositol-3 kinase and c-SRC inhibitors prevented TSP-1- and HyA-induced migration, whereas Ras and Raf-1 kinase inhibitors only affected TSP-1. TSP-1 and HyA activate the EGFR.

TSP-1- and HYA-induced migration share some of the same signaling pathways and the EGFR/CD44 receptors may be a common link.