Abstract
Aortic smooth muscle cells produce chondroitin/dermatan sulfate (CS/DS) proteoglycans that regulate extracellular matrix organization and cell behavior in normal and pathological conditions. A unique feature of CS/DS proteoglycans is the presence of iduronic acid (IdoA), catalyzed by two DS epimerases. Functional ablation of DS-epi1, the main epimerase in these cells, resulted in a major reduction of IdoA both on cell surface and in secreted CS/DS proteoglycans. Downregulation of IdoA led to delayed ability to re-populate wounded areas due to loss of directional persistence of migration. DS-epi1−/− aortic smooth muscle cells, however, had not lost the general property of migration showing even increased speed of movement compared to wild type cells. Where the cell membrane adheres to the substratum, stress fibers were denser whereas focal adhesion sites were fewer. Total cellular expression of focal adhesion kinase (FAK) and phospho-FAK (pFAK) was decreased in mutant cells compared to control cells. As many pathological conditions are dependent on migration, modulation of IdoA content may point to therapeutic strategies for diseases such as cancer and atherosclerosis.
Highlights
Proteoglycans (PGs) consist of glycosaminoglycan (GAG) chains attached to core proteins, and PGs can be found either in the extracellular space or bound to the cell membrane
Purified chondroitin/dermatan sulfate (CS/DS) was digested by chondroitinase B, which cleaves GalNAc,iduronic acid (IdoA) linkages, or by a mixture of chondroitinase ACI+ACII, which cleave GalNAc,glucuronic acid (GlcA) linkages
In this report we show that, following dermatan sulfate epimerase 1 (DS-epi1) ablation, an IdoA decrease in CS/DS on the cell surface results in changed spreading and diminished directional migration of aortic smooth muscle cells (AoSMCs)
Summary
Proteoglycans (PGs) consist of glycosaminoglycan (GAG) chains attached to core proteins, and PGs can be found either in the extracellular space or bound to the cell membrane. Cell membrane-bound PGs may act as co-receptors and regulate biological processes such as proliferation, adhesion and migration, and these effects are mostly due to the PGs’ ability to interact and modulate the activity of growth factors, cytokines [1,2] and integrins [3]. Two major types of GAGs, chondroitin/dermatan sulfate (CS/ DS) and heparan sulfate (HS), are characteristic components of PGs. CS/DS chains are polymers consisting of repeated units of glucuronic acid (GlcA) or its epimer iduronic acid (IdoA) and Nacetyl-galactosamine (GalNAc). The action of DS-epi and 2 together with O-sulfotransferases [7], adding sulfate groups in 2-O position of IdoA/GlcA and 4-O and/or 6-O of GalNAc, produce a set of different structures that confer further complexity to the CS/DS chains. The IdoA regions are mainly 4O-sulfated due to the strong stimulatory effect of dermatan sulfate 4-O-sulfotransferase 1 on IdoA formation [8]
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