CCL23 up-regulates expression of KDR/Flk-1 and potentiates VEGF-induced proliferation and migration of human endothelial cells

CCL23 is a CC chemokine and exerts its biological activities on endothelial cells as well as on immune cells through CCR1. We investigated the potential effect of CCL23 on expression of VEGFR2/KDR/Flk-1/VEGFR2/KDR/Flk-1 receptor in endothelial cells. PCR, confocal microscope and Western blot analysis revealed that CCL23 up-regulated VEGFR2/KDR/Flk-1/VEGFR2/KDR/Flk-1 mRNA and protein levels in endothelial cells. A reporter assay indicated that CCL23-induced VEGFR2/KDR/Flk-1/VEGFR2/KDR/Flk-1 expression primarily occurred at the transcriptional level. In addition, CCL23 stimulated phosphorylation of SAPK/JNK, and an inhibitor of SAPK/JNK blocks the CCL23-induced VEGFR2/KDR/Flk-1/VEGFR2/KDR/Flk-1 expression. Furthermore, VEGF-induced ERK phosphorylation was stimulated by CCL23. Finally, CCL23 promoted VEGF-induced endothelial proliferation and migration, which were correlated with the maximal stimulation of VEGFR2/KDR/Flk-1/VEGFR2/KDR/Flk-1 expression by CCL23. Taken together, these findings suggest that CCL23 results in up-regulation of VEGFR2/KDR/Flk-1/VEGFR2/KDR/Flk-1 receptor gene transcription and protein expression and that VEGFR2/KDR/Flk-1/VEGFR2/KDR/Flk-1 up-regulation induced by CCL23 may contribute to potentiation of VEGF action in angiogenesis.