ERK1-2 and p38 MAPK regulate MMP/TIMP balance and function in response to thrombospondin-1 fragments in the microvascular endothelium

Sandra Donnini, Lucia Morbidelli, Giulia Taraboletti, Marina Ziche

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2975-2985
Number of pages11
JournalLife Sciences
Volume74
Issue number24
DOIs
Publication statusPublished - Apr 30 2004

Fingerprint

Thrombospondin 1
Tissue Inhibitor of Metalloproteinases
Matrix Metalloproteinase Inhibitors
p38 Mitogen-Activated Protein Kinases
Matrix Metalloproteinases
Endothelium
Mitogen-Activated Protein Kinases
Tissue Inhibitor of Metalloproteinase-2
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Chemical activation
Endothelial cells
Fibroblast Growth Factor 2
Peptide Hydrolases
Up-Regulation
Endothelial Cells
Switches
Phenotype

Keywords

  • Angiogenesis
  • Endothelium
  • ERK1-2
  • Metalloproteinases

ASJC Scopus subject areas

  • Pharmacology

Cite this

ERK1-2 and p38 MAPK regulate MMP/TIMP balance and function in response to thrombospondin-1 fragments in the microvascular endothelium. / Donnini, Sandra; Morbidelli, Lucia; Taraboletti, Giulia; Ziche, Marina.

In: Life Sciences, Vol. 74, No. 24, 30.04.2004, p. 2975-2985.

Research output: Contribution to journalArticle

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