Sphingosine-1-phosphate-induced release of TIMP-2 from vascular smooth muscle cells inhibits angiogenesis

Keith Stewart Mascall, Gary R. Small, George Gibson, Graeme Fleming Nixon

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Following myocardial infarction, as a result of thrombus formation, angiogenesis occurs and permits reperfusion of damaged myocardium. Sphingosine 1-phosphate (S1P) is a naturally occurring lipid mediator released from platelets and is found in high concentrations at sites of thrombosis. S1P may therefore be involved in regulating angiogenesis following myocardial infarction and may influence reperfusion. The aims of this study were to determine the effects of S1P in human coronary arterial cell angiogenesis and delineate the subsequent mechanisms.An in vitro model of angiogenesis was developed using a co-culture of human coronary artery endothelial cells, human coronary smooth muscle cells and human fibroblasts. In this model S1P inhibited angiogenesis and this was dependent on the presence of smooth muscle cells. The mechanism of the inhibitory effect was via S1P-induced release of a soluble mediator from smooth muscle cells. This mediator was identified as tissue inhibitor of metalloproteinase-2 (TIMP-2). TIMP-2 release was dependent on S1P-induced activation of Rho-kinase and directly contributed to incomplete formation of endothelial cell adherens junctions. This was observed as a diffuse localization of VE-cadherin leading to decreased tubulogenesis. A similar inhibitory response to S1P was demonstrated in an ex vivo human arterial model of angiogenesis.In summary, S1P-induced inhibition of angiogenesis in human artery endothelial cells is mediated by TIMP-2 from vascular smooth muscle cells. This reduces the integrity of intercellular junctions between nascent endothelial cells. S1P may therefore inhibit the angiogenic response following myocardial infarction.
Original languageEnglish
Pages (from-to)2267-2275
Number of pages9
JournalJournal of Cell Science
Volume125
Issue number9
Early online date17 Feb 2012
DOIs
Publication statusPublished - 1 May 2012

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Tissue Inhibitor of Metalloproteinase-2
Vascular Smooth Muscle
Smooth Muscle Myocytes
Endothelial Cells
Intercellular Junctions
Myocardial Infarction
Reperfusion
Thrombosis
Adherens Junctions
sphingosine 1-phosphate
rho-Associated Kinases
Coculture Techniques
Coronary Vessels
Myocardium
Blood Platelets
Arteries
Fibroblasts
Lipids

Keywords

  • angiogenesis
  • sphingosine 1-phosphate
  • vascular smooth muscle
  • metalloproteinase

Cite this

Sphingosine-1-phosphate-induced release of TIMP-2 from vascular smooth muscle cells inhibits angiogenesis. / Mascall, Keith Stewart; Small, Gary R.; Gibson, George; Nixon, Graeme Fleming.

In: Journal of Cell Science, Vol. 125, No. 9, 01.05.2012, p. 2267-2275.

Research output: Contribution to journalArticle

Mascall, Keith Stewart ; Small, Gary R. ; Gibson, George ; Nixon, Graeme Fleming. / Sphingosine-1-phosphate-induced release of TIMP-2 from vascular smooth muscle cells inhibits angiogenesis. In: Journal of Cell Science. 2012 ; Vol. 125, No. 9. pp. 2267-2275.
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AB - Following myocardial infarction, as a result of thrombus formation, angiogenesis occurs and permits reperfusion of damaged myocardium. Sphingosine 1-phosphate (S1P) is a naturally occurring lipid mediator released from platelets and is found in high concentrations at sites of thrombosis. S1P may therefore be involved in regulating angiogenesis following myocardial infarction and may influence reperfusion. The aims of this study were to determine the effects of S1P in human coronary arterial cell angiogenesis and delineate the subsequent mechanisms.An in vitro model of angiogenesis was developed using a co-culture of human coronary artery endothelial cells, human coronary smooth muscle cells and human fibroblasts. In this model S1P inhibited angiogenesis and this was dependent on the presence of smooth muscle cells. The mechanism of the inhibitory effect was via S1P-induced release of a soluble mediator from smooth muscle cells. This mediator was identified as tissue inhibitor of metalloproteinase-2 (TIMP-2). TIMP-2 release was dependent on S1P-induced activation of Rho-kinase and directly contributed to incomplete formation of endothelial cell adherens junctions. This was observed as a diffuse localization of VE-cadherin leading to decreased tubulogenesis. A similar inhibitory response to S1P was demonstrated in an ex vivo human arterial model of angiogenesis.In summary, S1P-induced inhibition of angiogenesis in human artery endothelial cells is mediated by TIMP-2 from vascular smooth muscle cells. This reduces the integrity of intercellular junctions between nascent endothelial cells. S1P may therefore inhibit the angiogenic response following myocardial infarction.

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