BACKGROUND: Vascular branching morphogenesis is responsible for the extension of blood vessels into growing tissues, a process crucial for organogenesis. However, the genetic mechanism for vessel branching is largely unknown. Zebrafish reg6 is a temperature-sensitive mutation exhibiting defects in blood vessel branching which results in the formation of swollen vessel lumina during capillary plexus formation. Results: We performed a screening for chemical suppressors of reg6 and identified SKF91488, an inhibitor of histamine methyltransferase (HMT), that can rescue the reg6 vessel branching defects in a dose-dependent manner. Inhibition of HMT by SKF91488 presumably blocks histamine degradation, thus causing histamine accumulation. Consistent with this idea, we found that a high level of histamine also showed significant suppression of reg6 vessel phenotypes. Interestingly, when reg6 adults that had already developed swollen vessel luation, thus causing histamine accumulation. Consistent with this idea, we found that a high level of histamine also showed significant suppressiomina in regenerating fins were treated with histamine or SKF91488, either treatment significantly reduced the number of swollen vessels within 12 h, suggesting a rapid and constant influence of histamine on blood vessel branching. Furthermore, the expression of HMT was significantly elevated in reg6 regenerating fins. Conversely, lowering histamine by administering urocanic acid, a histidine decarboxylase inhibitor, enhanced the reg6 phenotypes. Finally, we identified that the transcription factor, egr-1 (early growth response factor 1), was closely associated with the reg6 phenotype and chemical treatments. Conclusions: Taken together, our results suggest that blood vessel branching is influenced by histamine metabolism, likely through regulating the expression of the egr-1 transcription factor.