title: CCL2 regulates angiogenesis via activation of Ets-1 transcription factor.
abstract: Although recent studies have suggested that CC chemokine CCL2 may directly affect the angiogenesis, the signaling events involved in such regulation remain to be determined. This study investigated a potential signal mechanism involved in CCL2-induced angiogenesis. Our in vitro and in vivo (hemangioma model of angiogenesis) experiments confirmed earlier findings that CCL2 can induce angiogenesis directly. Using a gene array analysis, CCL2 was found to induce expression of several angiogenic factors in brain endothelial cells. Among the most prominent was an up-regulation in Ets-1 transcription factor. CCL2 induced a significant increase in Ets-1 mRNA and protein expression as well as Ets-1 DNA-binding activity. Importantly, Ets-1 antisense oligonucleotide markedly abrogated in vitro CCL2-induced angiogenesis, suggesting that Ets-1 is critically involved in this process. Activation of Ets-1 by CCL2 further regulated some of Ets-1 target molecules including beta(3) integrins. CCL2 induced significant up-regulation of beta(3) mRNA and protein expression, and this effect of CCL2 was prevented by the Ets-1 antisense oligonucleotide. The functional regulation of Ets-1 activity by CCL2 was dependent on ERK-1/2 cascade. Inhibition of ERK1/2 activity by PD98509 prevented CCL2-induced increases in Ets-1 DNA-binding activity and Ets-1 mRNA expression. Based on these findings, we suggest that Ets-1 transcription factor plays a critical role in CCL2 actions on brain endothelial cells and CCL2-induced angiogenesis.
authors.affiliation: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Svetlana M
authors.initials: SM
authors.lastname: Stamatovic
authors.forename: Richard F
authors.initials: RF
authors.lastname: Keep
authors.forename: Marija
authors.initials: M
authors.lastname: Mostarica-Stojkovic
authors.forename: Anuska V
authors.initials: AV
authors.lastname: Andjelkovic
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002461:Cell Line, Transformed; D018932:Chemokine CCL2 / Q000502:physiology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006391:Hemangioma / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000276:immunology; D018919:Neovascularization, Physiologic / Q000276:immunology*; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C494042:Ets1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1