Mechanisms of angiotensin-(1–7)-induced inhibition of angiogenesis

Abstract

Angiotensin-(1–7) [ANG-(1–7)], an endogenous bioactive peptide constituent of the renin-angiotensin system, acts as an inhibitory growth factor in vitro and in vivo. In this study, we evaluated whether the antiangiogenic effect of ANG-(1–7) in the mouse sponge model of angiogenesis might be receptor mediated and involved in the release of nitric oxide (NO). The hemoglobin content (μg/mg wet tissue) of 7-day-old sponge implants was used as an index of the vascularization and showed that daily injections of ANG-(1–7) (20 ng) inhibited significantly the angiogenesis in the implants relative to the saline-treated group. The specific receptor antagonistd-Ala7-ANG-(1–7); A-779 prevented ANG-(1–7)-induced inhibition of angiogenesis. The antiangiogenic effect was also abolished by pretreatment with NO synthase inhibitors aminoguanidine (1 mg/ml) or N G-nitro-l-arginine methyl ester (0.3 mg/ml). Selective AT1 and AT2angiotensin-receptor antagonists and an angiotensin-converting enzyme inhibitor, in combination with ANG-(1–7) or alone, did not alter angiogenesis in the implants. These results establish that the regulation of the vascular tissue growth by ANG-(1–7) is associated with NO release by activation of an angiotensin receptor distinct from AT1 and AT2.