Decorin inhibits endothelial migration and tube-like structure formation: role of thrombospondin-1.
Interactions between endothelial cell receptors and the extracellular matrix (ECM) play a critical, yet poorly understood role in angiogenesis. Based on the anti-adhesive role of decorin, we hypothesized that decorin binding to ECM molecules such as thrombospondin-1 (TSP-1) plays a regulatory role in endothelial tube-like structure (TLS) formation. To test this hypothesis, endothelial cells were plated on TSP-1, decorin, or mixed substrates of TSP-1 plus decorin. TLS formation was induced by applying type I collagen on the confluent endothelial monolayer. Cartilage decorin inhibited the formation of TLSs in a concentration-dependent manner. On substrates of high decorin concentrations (2.5 and 5.0 microg/cm(2)) the reduction in TLSs was due either to a reduction in the number of adhering cells or to decreased cell migration. At low decorin concentrations (0.05 and 0.25 microg/cm(2)) the reduction in TLSs was independent of the number of attached cells. Time-lapse video microscopy revealed that decorin substrates facilitated homotypic aggregation and isolated cord formation at the expense of endothelial migration and TLS formation. Consistent with the reduced migration, endothelial cells formed fewer vinculin-positive focal adhesions and actin-stress fibers on decorin substrates. Endothelial migration and TLS formation were also significantly inhibited by skin decorin and the protein core of cartilage decorin. The inhibition of TLS formation by the protein core of cartilage decorin was potentiated by TSP-1. These findings suggest that decorin alone or in combination with TSP-1 interferes with the activation of endothelial cell receptors by ECM molecules, thus blocking intracellular signals that induce cytoskeletal reorganization, migration, and TLS formation.
Davies
C de L
Cde L
Department of Physics, Norwegian University of Science and Technology, Trondheim, N-7491, Norway.
Melder
R J
RJ
Munn
L L
LL
Mouta-Carreira
C
C
Jain
R K
RK
Boucher
Y
Y
D002356:Cartilage / Q000737:chemistry; D002448:Cell Adhesion / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D048429:Cell Size; D002478:Cells, Cultured; D058575:Decorin; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D016326:Extracellular Matrix Proteins; D005353:Fibronectins / Q000494:pharmacology; D022001:Focal Adhesions / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D018613:Microscopy, Confocal; D018715:Microscopy, Video; D011509:Proteoglycans / Q000494:pharmacology* / Q000502:physiology; D022502:Stress Fibers / Q000378:metabolism / Q000648:ultrastructure; D019700:Thrombospondin 1 / Q000494:pharmacology* / Q000502:physiology
C546878:DCN protein, human; D058575:Decorin; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D011509:Proteoglycans; D019700:Thrombospondin 1