Following myocardial infarction, as a result of thrombus formation, angiogenesis occurs and permits reperfusion of damaged myocardium. Sphingolipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) are naturally occurring lipid mediators released from platelets and found in high concentrations at sites of thrombosis. S1P and SPC 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 and SPC 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 and SPC inhibited angiogenesis and this was dependent on the presence of smooth muscle cells. The mechanism of the inhibitory effect was via S1P-/SPC-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 sphingolipid-induced activation of S1P2 receptor and Rho-kinase signalling 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. This effect may occur via both matrix metalloproteinase-dependent and/or matrix metalloproteinase-independent pathways. A similar inhibitory response to S1P was demonstrated in ex vivo human and mouse arterial models of angiogenesis. In summary, S1P- and SPC-induced inhibition of angiogenesis in human artery endothelial cells mediated by TIMP-2 from vascular smooth muscle cells. This reduces the integrity of intercellular junctions between nascent endothelial cells. S1P and SPC may therefore inhibit the angiogenic response following myocardial infarction.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:560885 |
| Date | January 2012 |
| Creators | Mascall, Keith S. |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=189442 |
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