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 (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.

Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7)

“…Antiangiogenic properties of Ang-(1-7), first described by Machado et al, 58,59 and those reported by us on protein synthesis 35,60 endow this peptide with antitumoral properties since Gallagher and Tallant 61 showed that Ang-(1-7) inhibits growth in 3 human lung cancer cell lines (human adenocarcinoma SK-LU-1, A549 cells, and non-small lung cancer SK-MES-1 cells). Treatment with Ang-(1-7) resulted in both a dose-and time-dependent reduction in serum-stimulated DNA synthesis in all 3 of the cell lines, with an IC 50 in the subnanomolar range.…”

Angiotensin II AT1 receptors regulate ACE2 and angiotensin-(1–7) expression in the aorta of spontaneously hypertensive rats

“…Studies from our laboratory documented that ANG-(1-7) reverses neointimal growth induced by denudation of the vascular endothelium of a carotid artery (29) through a non-AT 1 /AT 2 receptor (16). Additional antiangiogenic effects of ANG-(1-7) were documented in a mouse sponge model of angiogenesis, whereby ANG-(1-7) inhibited vessel formation within the implant (24,25). There is evidence that ANG-(1-7) contributes to the antihypertensive effect produced by blockers of the RAS because blockade of ANG-(1-7) receptors with a selective receptor antagonist or a selective ANG-(1-7) antibody reversed the antihypertensive effect mediated by chronic administration of lisinopril and losartan in rats (22).…”

Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation

“…There was evidence suggesting that the AT 2 receptor mediates ANG-(1-7)-induced relaxation of porcine coronary arteries associated with NO and kinins (Gorelik et al, 1998). It was suggested that the antiangiogenic effect of ANG-(1-7) in the mouse sponge model of angiogenesis is associated with NO release by activation of an ANG receptor distinct from AT 1 and AT 2 (Machado et al, 2001). In preexisting (skin) and newly formed vasculature (14-day-old polyurethane sponge implants) in mice, ANG-(1-7)-induced vasodilator effects was prevented by the specific receptor antagonist (D-Ala 7 )-ANG-(1-7) and abolished by NOS inhibitors, suggesting that this peptide contributes to the vasodilatation via NO also in newly formed vascular beds (Machado et al, 2002).…”