We have analyzed the role of histamine in the angiogenesis of the granulation tissue in histidine decarboxylase-deficient (HDC-/-) mice, mast cell-deficient mice (WBB6F1-W/Wv), and their corresponding wild-type mice (HDC+/+ and WBB6F1+/+). In HDC+/+ mice, subcutaneous implantation of a cotton thread in the dorsum induced granulation tissue formation with angiogenesis, while the topical injection of antivascular endothelial growth factor (VEGF) IgG strongly suppressed them. In HDC-/- mice which showed lower VEGF levels in the granulation tissue, there was notably less angiogenesis and granulation tissue formation than in HDC+/+ mice. The topical injection of histamine or the H2 agonist dimaprit rescued the defective angiogenesis and granulation tissue formation in HDC-/- mice. There was no significant difference in the granulation tissue formation and angiogenesis between WBB6F1-W/WV and WBB6F1÷/+ mice. In addition, macrophages in the granulation tissue were found to express HDC. Our findings indicate that histamine derived from nonmast cells plays a significant role in the angiogenesis of the inflammatory granulation tissue.
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