Stromal cell-derived factor 1 (SDF-1) regulates neovascularization, which is coordinately controlled by endothelial cells (EC) and their surrounding cells, pericytes or smooth muscle cells. In the basal state, SDF-1 expression is much lower in EC than in their surrounding cells. In this study, we evaluated epigenetic regulation to determine if it is involved in the mechanism responsible for the differential expression of SDF-1 in two types of vascular cells, brain microvascular EC (HBMEC) and, pericytes (HBMP). We found that HBMEC did not express SDF-1, but that HBMP did. Furthermore, treatment of EC with 5-aza-2'-dexoycytidine and trichostatin A resulted in a remarkable restoration of SDF-1 expression. Additionally, bisulfite-sequencing analysis revealed no differences in the methylation state of SDF-1 promoter between HBMEC and HBMP. Finally, a chromatin immunoprecipitation assay revealed reduced levels of histone H3 lysine 9 (H3K9) acetylation and H3K4 trimethylation with concomitant enhancement of H3K9 trimethylation in HBMEC relative to HBMP, which suggests that histone modifications are involved in the cell-specific expression of SDF-1. (C) 2009 Elsevier Inc. All rights reserved.