Abstract 15048: The Cellular Repressor of E1a-Stimulated Genes Regulates Endothelial Filopodia Formation and Angiogenesis
Abstract The regulation of blood vessel formation is of fundamental importance to many physiological processes, and angiogenesis is a major area for novel therapeutic approaches to diseases from ischemia to cancer. However, the mechanisms that mediate angiogenesis have not been fully understood. The cellular repressor of E1A-stimulated genes (CREG) is an important endothelial-protective gene. Our previous study revealed that CREG is abundantly expressed in the adult vascular endothelium and dramatically reduced in the atherosclerotic endothelium, which is associated with wound healing and re-endothelialization in injured arteries. A later study found that overexpression of CREG accelerates the mobility of endothelial cells via the integrin-linked kinase (ILK)/VEGF165 signaling pathway. In this study, we sought to investigate the role of CREG in angiogenesis and its underlying molecular mechanisms. Overexpression of CREG in human umbilical vein endothelial cells with the adenovirus vector caused excessive angiogenic branching and network formation in vitro (3D sprouting angiogenesis) and in vivo, which was accompanied by more filopodia formation and a change in cell shape. Further studies showed that ILK participated in CREG-mediated endothelial filopodia formation. By transfecting the binding-site-mutant plasmids of ILK, we identified that CREG activates the ILK-β-parvin signaling pathway, which is involved in the formation of filopodia to induce vessel branching and sprouting in angiogenesis. More importantly, we identified that p-cdc42 and glycogen synthase kinase-3β (GSK-3β), are key downstream molecules involved in CREG-mediated endothelial cell filopodia formation following NSC23766 (a cdc42 inhibitor) and lithium (a GSK-3β inhibitor) treatment. In conclusion, CREG overexpression promotes endothelial filopodia formation to regulate angiogenesis via the ILK/beta-parvin/p-cdc42/GSK-3β signaling pathway. Overall, our results will provide further insights for future research in the field of angiogenesis.
- © 2012 by American Heart Association, Inc.