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 (microg/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 antagonist D-Ala(7)-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 AT2 angiotensin-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.

No abstract

No abstract

Stimulators of angiogenesis hold potential in promoting the development of collateral circulation in ischaemic tissue and accelerating wound healing, but promote pathological vasoformation in angiogenesis-dependent diseases (solid tumours, atherosclerosis). The renin-angiotensin system is implicated in both beneficial angiogenesis and pathological vascular growth. We investigated the angiogenic activity of angiotensin II (All) in a sponge implant model in mice; this peptide enhanced angiogenesis, as well as glycosaminoglycan (GAG, chondroitin sulfate proteoglycan) and protein synthesis in sponge matrix in mice in a dose-dependent fashion. Extensive angiogenesis was achieved with All (1 µg), which gave no significant increase in wet weight and protein and only a small effect on GAG. In the implants treated with All (2 µg) no further increase in angiogenesis was observed, whereas a marked effect was shown in wet weight (326 ± 15 vs. 424 ± 27 mg), total protein (18 ± 1 vs. 25 ± 1 µg/ww) and GAG(98 ± 10 vs. 160 ± 13 ng/ww). The local blood flow has been determined by measuring the washout rate of ¹³³Xe injected into the implants, correlated with histological evidence of vessel growth. This model of angiogenesis has allowed sequential studies of fibrovascular tissue infiltration simultaneously with histological and biochemical parameters of angiogenesis.

No abstract