title: Matrix metalloproteinase regulation of sphingosine-1-phosphate-induced angiogenic properties of bone marrow stromal cells.
abstract: OBJECTIVE
  Bone marrow-derived stromal cells (MSC) are able to acquire histological and immunophenotypic characteristics consistent with endothelial cells (EC). In this study we examined the effect of sphingosine-1-phosphate (S1P), a platelet-derived bioactive lysophospholipid that is believed to specifically stimulate EC migration and tube formation, on the angiogenic properties of MSC.
  
  
  METHODS
  MSC were isolated from murine bone marrow and cultured in the presence of diverse angiogenic growth factors. Using a chemotaxis chamber and Matrigel tubulogenesis assay, we measured the extent of MSC migration and capillary-like structure formation. Western blots and zymography were used to assess the levels and activation states of soluble and membrane-bound matrix metalloproteinase (MMP).
  
  
  RESULTS
  We found that S1P strongly induced MSC migration and in vitro capillary-like structure formation. Ilomastat, a broad-spectrum MMP inhibitor, antagonized several angiogenic and S1P-mediated events in MSC. These included 1) the inhibition of S1P-induced tube formation, 2) the inhibition of concanavalin-A (Con-A)-mediated proMMP-2 activation, and 3) the inhibition of S1P- and Con-A-induced caspase-3 activity. Moreover, S1P induced membrane type-1 (MT1)-MMP mRNA and protein expression, but paradoxically antagonized its cell surface proteolytic processing. In addition, anti-angiogenic agents such as Ilomastat, Neovastat, and green tea polyphenol epigallocatechin-3-gallate antagonized the S1P-induced migration of MSC as well as that of transfected COS-7 cells overexpressing the recombinant receptor for S1P, EDG-1.
  
  
  CONCLUSIONS
  Collectively, our results indicate a crucial role for S1P/EDG-1-mediated angiogenic and survival events in the regulation of microvascular network remodeling by MSC, and may provide a new molecular link between hemostasis and angiogenesis processes.
authors.affiliation: Laboratoire de Médecine Moléculaire, Centre de Cancérologie Charles-Bruneau, Hôpital Sainte-Justine and Université du Québec à Montréal, Montreal, Quebec, Canada.
authors.forename: Borhane
authors.initials: B
authors.lastname: Annabi
authors.forename: Sébastien
authors.initials: S
authors.lastname: Thibeault
authors.forename: Ying-Ta
authors.initials: YT
authors.lastname: Lee
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bousquet-Gagnon
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Eliopoulos
authors.forename: Stéphane
authors.initials: S
authors.lastname: Barrette
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau
authors.forename: Richard
authors.initials: R
authors.lastname: Béliveau
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology*; D019556:COS Cells; D017931:DNA Primers; D004789:Enzyme Activation; D008246:Lysophospholipids; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology*
chemical_list: D017931:DNA Primers; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D020782:Matrix Metalloproteinases; D013110:Sphingosine