CCL2 Regulates Angiogenesis via Activation of Ets-1 Transcription Factor

• Published in: Journal of Immunology 2006-08, Vol.177 (4), p.2651-2661
• Main Authors: Stamatovic, Svetlana M, Keep, Richard F, Mostarica-Stojkovic, Marija, Andjelkovic, Anuska V
• Format: Article
• Language: English
• Subjects: Animals; Brain - blood supply; Brain - cytology; Brain - immunology; Brain - metabolism; Cell Line, Transformed; Chemokine CCL2 - physiology; Disease Models, Animal; Endothelial Cells - immunology; Endothelial Cells - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - immunology; Endothelium, Vascular - metabolism; Hemangioma - immunology; Hemangioma - metabolism; Male; Mice; Mice, Nude; Neovascularization, Pathologic - immunology; Neovascularization, Physiologic - immunology; Proto-Oncogene Protein c-ets-1 - metabolism; Proto-Oncogene Protein c-ets-1 - physiology; Signal Transduction - immunology; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.177.4.2651

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.