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Title: Novel role of lactosylceramide in vascular endothelial growth factor-mediated angiogenesis in human endothelial cells
Authors: Rajesh, M. 
Kolmakova, A.
Chatterjee, S. 
Keywords: Angiogenesis
Platelet endothelial cell adhesion molecule-1
Vascular endothelial growth factor
Issue Date: 14-Oct-2005
Citation: Rajesh, M., Kolmakova, A., Chatterjee, S. (2005-10-14). Novel role of lactosylceramide in vascular endothelial growth factor-mediated angiogenesis in human endothelial cells. Circulation Research 97 (8) : 796-804. ScholarBank@NUS Repository.
Abstract: Vascular endothelial growth factor (VEGF) has been implicated in angiogenesis associated with coronary heart disease, vascular complications in diabetes, inflammatory vascular diseases, and tumor metastasis. The mechanism of VEGF-driven angiogenesis involving glycosphingolipids such as lactosylceramide (LacCer), however, is not known. To demonstrate the involvement of LacCer in VEGF-induced angiogenesis, we used small interfering RNA (siRNA)-mediated silencing of LacCer synthase expression (GalT-V) in human umbilical vein endothelial cells. This gene silencing markedly inhibited VEGF-induced platelet endothelial cell adhesion molecule-1 (PECAM-1) expression and angiogenesis. Second, we used D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of LacCer synthase and glucosylceramide synthase, that significantly mitigated VEGF-induced PECAM-1 expression and angiogenesis. Interestingly, these phenotypic changes were reversed by LacCer but not by structurally related compounds such as glucosylceramide, digalactosylceramide, and ceramide. In a human mesothelioma cell line (REN) that lacks the endogenous expression of PECAM-1, VEGF/LacCer failed to stimulate PECAM-1 expression and tube formation/angiogenesis. In REN cells expressing human PECAM-1 gene/protein, however, both VEGF and LacCer-induced PECAM-1 protein expression and tube formation /angiogenesis. In fact, VEGF-induced but not LacCer-induced angiogenesis was mitigated by SU-1498, a VEGF receptor tyrosine kinase inhibitor. Also, VEGF/LacCer induced PECAM-1 expression and angiogenesis was mitigated by protein kinase C and phospholipase A 2 inhibitors. These results indicate that LacCer generated in VEGF-treated endothelial cells may serve as an important signaling molecule for PECAM-1 expression and in angiogenesis. This finding and the reagents developed in our report may be useful as anti-angiogenic drugs for further studies in vitro and in vivo. © 2005 American Heart Association, Inc.
Source Title: Circulation Research
ISSN: 00097330
DOI: 10.1161/01.RES.0000185327.45463.A8
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