Enhancement by histamine of vascular endothelial growth factor production in granulation tissue via H2 receptors

1 Roles of histamine in the production of vascular endothelial growth factor (VEGF) in the carrageenin-induced granulation tissue in rats were analysed in vitro and in vivo. 2 Incubation of the minced granulation tissue in the presence of histamine (1 and 10 muM) increased the content of VEGF protein in the conditioned medium in a time- and concentration-dependent manner. The levels of VEGF mRNA in the minced granulation tissue were also increased by histamine in a concentration-dependent manner. 3 The increase in the content of VEGF protein in the conditioned medium by histamine (10 muM) was suppressed by the H-2 receptor antagonist cimetidine (IC50 0.37 muM), but not by the H-1 receptor antagonist pyrilamine maleate, the H-3 receptor antagonist thioperamide or the cyclo-oxygenase inhibitor indomethacin. 4 The histamine-induced increase in the content of VEGF protein in the conditioned medium was inhibited by the cyclic AMP antagonist Rp-cAMP (IC50 6.8 muM), and the protein kinase A inhibitor H-89 (IC50 12.5 muM), but not by the protein kinase C inhibitors Ro 31-8425 and calphostin C or the tyrosine kinase inhibitor genistein. 5 Simultaneous injection of cimetidine (400 mug) and indomethacin (100 mug) into the air pouch of rats additively reduced the carrageenin-induced increase in VEGF protein levels and angiogenesis in the granulation tissue as assessed by using carmine dye. 6 These findings indicate that histamine has an activity to induce VEGF production in the granulation tissue via the H-2 receptor-cyclic AMP-protein kinase A pathway and augments angiogenesis in the granulation tissue.