title: Inhibition of endothelial cell migration by thrombospondin-1 type-1 repeats is mediated by beta1 integrins.
abstract: The anti-angiogenic effect of thrombospondin-1 has been shown to be mediated through binding of the type-1 repeat (TSR) domain to the CD36 transmembrane receptor. We now report that the TSR domain can inhibit VEGF-induced migration in human umbilical vein endothelial cells (HUVEC), cells that lack CD36. Moreover, we identified beta1 integrins as a critical receptor in TSR-mediated inhibition of migration in HUVEC. Using pharmacological inhibitors of downstream VEGF receptor effectors, we found that phosphoinositide 3-kinase (PI3k) was essential for TSR-mediated inhibition of HUVEC migration, but that neither PLCgamma nor Akt was necessary for this response. Furthermore, beta1 integrins were critical for TSR-mediated inhibition of microvascular endothelial cells, cells that express CD36. Together, our results indicate that beta1 integrins mediate the anti-migratory effects of TSR through a PI3k-dependent mechanism.
authors.affiliation: Vascular Biology Program, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Short
authors.forename: Alexandrine
authors.initials: A
authors.lastname: Derrien
authors.forename: Radha P
authors.initials: RP
authors.lastname: Narsimhan
authors.forename: Jack
authors.initials: J
authors.lastname: Lawler
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ingber
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Zetter
mesh_terms: D018955:CD36 Antigens / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019700:Thrombospondin 1 / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D019012:Integrin beta1; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D019700:Thrombospondin 1; D010738:Type C Phospholipases; D042461:Vascular Endothelial Growth Factor A; C494918:AKT1 protein, human
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