Chymase as a proangiogenic factor - A possible involvement of chymase-angiotensin-dependent pathway in the hamster sponge angiogenesis model

We investigated the profound involvement of chymase, an alternative angiote nsin II-generating enzyme, in angiogenesis using a hamster sponge implant m odel. In vivo transfection of human pro-chymase cDNA or a direct injection of purified chymase into the sponges implanted resulted in marked increment of hemoglobin contents in the sponge granuloma tissues, demonstrating that chymase has an ability to elicit angiogenesis and is a potent angiogenic f actor. Daily injection of basic fibroblast growth factor into the sponges i mplanted also induced angiogenesis, which was suppressed by the treatment w ith chymostatin, an inhibitor of chymase, or TCV-116, an antagonist of angi otensin II (Ang II) type 1 receptor. Expression of chymase mRNA and product ion of Ang II in the granuloma tissues were enhanced by the stimulation wit h basic fibroblast growth factor. Chymase activity in the sponge granulomas increased in parallel with the rise in hemoglobin contents, and mast cells observed in the granuloma tissues were positively stained with anti-chymas e antibody, Exogenous administration not only of Ang II but of angiotensin I (Ang I) directly into the sponges could enhance angiogenesis. Chymostatin inhibited the angiogenesis induced by Ang I but not Ang II, suggesting the presence of a chymase-like Ang II-generating activity in the sponge granul omas. Our results may suggest a potential ability of chymase to promote ang iogenesis through the local chymase-dependent and angiotensin-converting en zyme-dependent Ang II generating system in pathophysiological angiogenesis.