OBJECTIVE: Arterial injury induces smooth muscle cell (SMC) proliferation, migration, and intimal accumulation of cells and extracellular matrix. These processes are regulated by the administration of the glycosaminoglycans heparin and heparan sulfate, but little is known about the role of endogenous heparan sulfate proteoglycans in the vessel wall. We investigated the response to carotid injury of syndecan-1-null mice to assess the function of one of a conserved family of transmembrane heparan and chondroitin sulfate proteoglycans. METHODS AND RESULTS: Syndecan-1-null mice developed a large neointimal lesion after injury, whereas wild-type mice made little or none. This was accompanied by a significant increase in both medial and intimal SMC replication. Cultured syndecan-1-null SMCs showed a significant increase in proliferation in response to PDGF-BB, thrombin, FGF2, EGF, and serum. In response to thrombin, PDGF-BB, and serum syndecan-1-null SMCs expressed more PDGF-B chain message than did wild-type SMCs. Downregulation of PDGF-BB or PDGFRbeta inhibited thrombin-, PDGF-BB-, and serum-induced DNA synthesis in syndecan-1-null SMCs. CONCLUSIONS: These results suggest the possibility that syndecan-1 may limit intimal thickening in injured arteries by suppressing SMC activation through inhibition of SMC PDGF-B chain expression and PDGFRbeta activation.
OBJECTIVE:Arterial injury induces smooth muscle cell (SMC) proliferation, migration, and intimal accumulation of cells and extracellular matrix. These processes are regulated by the administration of the glycosaminoglycansheparin and heparan sulfate, but little is known about the role of endogenous heparan sulfate proteoglycans in the vessel wall. We investigated the response to carotid injury of syndecan-1-null mice to assess the function of one of a conserved family of transmembrane heparan and chondroitin sulfate proteoglycans. METHODS AND RESULTS:Syndecan-1-null mice developed a large neointimal lesion after injury, whereas wild-type mice made little or none. This was accompanied by a significant increase in both medial and intimal SMC replication. Cultured syndecan-1-null SMCs showed a significant increase in proliferation in response to PDGF-BB, thrombin, FGF2, EGF, and serum. In response to thrombin, PDGF-BB, and serum syndecan-1-null SMCs expressed more PDGF-B chain message than did wild-type SMCs. Downregulation of PDGF-BB or PDGFRbeta inhibited thrombin-, PDGF-BB-, and serum-induced DNA synthesis in syndecan-1-null SMCs. CONCLUSIONS: These results suggest the possibility that syndecan-1 may limit intimal thickening in injured arteries by suppressing SMC activation through inhibition of SMC PDGF-B chain expression and PDGFRbeta activation.
Authors: Kathleen R Braun; Allison M DeWispelaere; Steven L Bressler; Nozomi Fukai; Richard D Kenagy; Lihua Chen; Alexander W Clowes; Michael G Kinsella Journal: PLoS One Date: 2012-08-17 Impact factor: 3.240