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We investigated the angiogenic effect of chymase, an alternative angiotensin II-generating enzyme, on angiogenesis using hamster sponge implant model. Exogenous administration of angiotensin II (Ang II) or angiotensin I (Ang I) directly into the sponges enhanced angiogenesis, as determined from the hemoglobin contents in the sponge granuloma tissues. Chymostatin, an inhibitor of chymase, inhibited angiogenesis induced by Ang I but not by Ang II, suggesting the presence of a chymase-like Ang II-generating activity in the sponge granuloma. TCV-116 (5 mg/kg p.o.), an antagonist of Ang II type 1 receptor, and chymostatin suppressed bFGF-induced angiogenesis, suggesting the significance of the endogenous angiotensin system. Chymase activity in the sponge granuloma increased in parallel with the rise in hemoglobin contents induced by bFGF. We also examined the effects of direct administration of human pro-chymase gene or purified hamster chymase, and demonstrated that in vivo human pro-chymase gene transfection and direct injection of purified chymase enhanced angiogenesis, which was 50% inhibited by TCV-116. Sponge granulomas treated with Ang II was supressed by vascular endothelial growth factor (VEGF) antisense. Our results suggest that chymase enhanced angiogenesis partly through the local production of Ang II, followed by up-regulation of VEGF.

To study the effects of angiotensin (ANG) peptides on airway epithelial ion transport function, we evaluated the bioelectric properties of canine cultured tracheal epithelium under short-circuit conditions in vitro. Addition of ANG I, II and II dose-dependently increased short-circuit current (Isc) and transepithelial potential difference, an effect that was more pronounced with addition to the submucosal solution than to the mucosal solution, with rank order of potency of ANG II greater than or equal to ANG II much greater than ANG I. The ANG-induced increase in Isc was not altered by the Na channel blocker amiloride, but was greatly reduced by the CI channel blocker diphenylamine-2-carboxylate and Cl-free medium. The response of Isc to ANG I was reduced by MK422, an angiotensin converting enzyme inhibitor, in a dose-dependent fashion. These results suggest that ANG II and III selectively stimulate Cl secretion across airway epithelium and that ANG I may exert its effect after its conversion to ANG II by angiotensin converting enzyme.