ERK1-2 and p38 MAPK regulate MMP/TIMP balance and function in response to thrombospondin-1 fragments in the microvascular endothelium.
We found that thrombospondin-1 (TSP-1) has opposite functions on angiogenesis depending on the nature of the proteolytic fragment released in vivo by the action of proteases. We studied the effect of the 25 and 140 kDa fragments of TSP-1 generated by its proteolytic cleavage on the cascade of mitogen activated protein kinase (MAPK) activation and matrix-metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) function and expression in microvascular endothelium. Post-capillary endothelial cells (CVEC) isolated from bovine heart were used. The 25 kDa fragment enhanced the upregulation of MMP-2 and -9 and reduced TIMP-2 expression leading to CVEC chemoinvasion. Conversely, the 140 kDa fragment blocked MMP-2 and -9 stimulation and doubled TIMP-2 expression, leading to inhibition of endothelial chemoinvasion induced by fibroblast growth factor-2 (FGF-2). MAPK activity (ERK1-2) was induced by TSP-1 and by the 25 kDa fragment, but not by the 140 kDa fragment which, however, promoted MAPK p38 activation. This evidence indicates that fragments originating from TSP-1 switch the pro- or anti-angiogenic phenotype in endothelium by targeting MAPK cascades with opposite functions on MMP/TIMP balance.
Donnini
Sandra
S
Department of Molecular Biology, University of Siena, Via Aldo Moro, 2, 53100 Siena, Italy.
Morbidelli
Lucia
L
Taraboletti
Giulia
G
Ziche
Marina
M
D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010446:Peptide Fragments; D019700:Thrombospondin 1 / Q000494:pharmacology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D010446:Peptide Fragments; D019700:Thrombospondin 1; D019714:Tissue Inhibitor of Metalloproteinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases