Journal
BIOCHEMICAL PHARMACOLOGY
Volume 84, Issue 8, Pages 1014-1023Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2012.07.006
Keywords
thrombospondin-1; endothelial colony-forming cells; glycosaminoglycans; angiogenesis
Categories
Funding
- National Council for Scientific and Technological Development (CNPq, Ministry of Science, Technology and Innovation, Brazil)
- Coordination for the Improvement of Higher Level Personnel (CAPES, Ministry of Education, Brazil)
- Groupe d'Etude et de Recherches sur l'Hemostase (GEHT)
- Region Ile-de-France (CORDDIM)
- Leducq TransAtlantic Network of Excellence [04CVD01-LENA, 04CVD02 -LINAT]
- PPSUS/CNPq/FAPERJ [E-26/110.780/2010]
- CAPES/COFECUB, France [629/09]
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Thrombospondin-1 (TSP-1) gives rise to fragments that have both pro- and anti-angiogenic effects in vitro and in vivo. The TSP-HepI peptide (2.3 kDa), located in the N-terminal domain of TSP-1, has proangiogenic effects on endothelial cells. We have previously shown that TSP-1 itself exhibits a dual effect on endothelial colony-forming cells (ECFC) by enhancing their adhesion through its TSP-HepI fragment while reducing their proliferation and differentiation into vascular tubes (tubulogenesis) in vitro. This effect is likely mediated through CD47 binding to the TSP-1 C-terminal domain. Here we investigated the effect of TSP-HepI peptide on the angiogenic properties of ECFC in vitro and in vivo. TSP-HepI peptide potentiated FGF-2-induced neovascularisation by enhancing ECFC chemotaxis and tubulogenesis in a Matrigel plug assay. ECFC exposure to 20 mu g/mL of TSP-HepI peptide for 18 h enhanced cell migration (p < 0.001 versus VEGF exposure), upregulated alpha 6-integrin expression, and enhanced their cell adhesion to activated endothelium under physiological shear stress conditions at levels comparable to those of SDF-1 alpha. The adhesion enhancement appeared to be mediated by the heparan sulfate proteoglycan (HSPG) syndecan-4, as ECFC adhesion was significantly reduced by a syndecan-4-neutralising antibody. ECFC migration and tubulogenesis were stimulated neither by a TSP-HepI peptide with a modified heparin-binding site (S/TSP-HepI) nor when the glycosaminoglycans (GAGS) moieties were removed from the ECFC surface by enzymatic treatment. Ex vivo TSP-HepI priming could potentially serve to enhance the effectiveness of therapeutic neovascularisation with ECFC. (C) 2012 Elsevier Inc. All rights reserved.
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