The RAS (renin-angiotensin system) is integral to cardiovascular physiology; however, dysregulation of this system largely contributes to the pathophysiology of CVD (cardiovascular disease). It is well established that AngII (angiotensin II), the main effector of the RAS, engages the AT1R (angiotensin type 1 receptor) and promotes cell growth, proliferation, migration and oxidative stress, all processes which contribute to remodelling of the heart and vasculature, ultimately leading to the development and progression of various CVDs, including heart failure and atherosclerosis. The counter-regulatory axis of the RAS, which is centred on the actions of ACE2 (angiotensin-converting enzyme 2) and the resultant production of Ang-(1-7) [angiotensin-(1-7)] from AngII, antagonizes the actions of AngII via the receptor Mas, thereby providing a protective role in CVD. More recently, another ACE2 metabolite, Ang-(1-9) [angiotensin-(1-9)], has been reported to be a biologically active peptide within the counter-regulatory axis of the RAS. The present review will discuss the role of the counter-regulatory RAS peptides Ang-(1-7) and Ang-(1-9) in the cardiovascular system, with a focus on their effects in remodelling of the heart and vasculature.

The counter-regulatory axis of the renin-angiotensin system (RAS) is a novel therapeutic target in cardiovascular disease. Pathophysiological effects mediated via angiotensin II (Ang II) are well established in regulation of blood pressure, cardiac and vascular remodeling, and renal sodium handling, which lead to disorders such as hypertension and associated end-organ damage, atherosclerosis and heart failure. The counter-regulatory axis of the RAS is centered on the angiotensin-converting enzyme 2/angiotensin-1-7 (Ang-[1-7])/Mas receptor axis and has been shown to inhibit many detrimental phenotypes in cardiovascular disease. More recently, an alternative peptide, angiotensin-(1-9) (Ang-[1-9]), has been reported as a potential new member of this axis. This review will discuss the cardiovascular regulatory roles of Ang-(1-7) and Ang-(1-9) in the counter-regulatory axis of the RAS, and the potential for new therapeutic approaches in cardiovascular disease.

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Vascular smooth muscle cell (SMC) proliferation and migration underlie the pathogenesis of vein graft failure and in-stent restenosis. Current interventions inhibit both SMC and endothelial cell (EC) growth, leading to thrombosis and re-occlusion. Angiotensin II (AngII) is a key regulator of VSMC proliferation and migration. A counter-regulatory axis of the renin angiotensin system (RAS) has been identified which inhibits AngII and is centred around angiotensin converting enzyme2 and Ang-(1–7) acting at Mas. We recently reported Ang-(1–9) as a novel member of this axis, acting at the angiotensin type 2 receptor (AT2R) to inhibit cardiac remodelling. Here we investigated the role of Ang-(1–9) in human SMC and EC migration and proliferation and vascular injury in vivo, and compared it to Ang-(1–7).SMC and EC were isolated from human saphenous veins. To assess migration, EC and SMC were stimulated with Ang II and Ang-(1–9) or Ang-(1–7) +/- the AT1R, AT2R or Mas antagonists losartan, PD123,319 (PD) or A779, respectively, and a wound healing assay performed. To assess proliferation, EC and SMC were stimulated with fetal calf serum (FCS) and Ang-(1–9) or Ang-(1–7) ± losartan, PD or A779. Proliferation was assessed using MTS and Edu assays. An in vivo mouse model was established via wire injury to the carotid artery. Ang-(1–7) or Ang-(1–9) ± PD or A779 were delivered subcutaneously via minipumps and neointima (NI) formation quantified 28 days post injury.Ang-(1–9) and Ang-(1–7) inhibited Ang II induced VSMC migration (Ang II 98.9 ± 1.1%, Ang-(1–9) 43.3 ± 3.3% and Ang-(1–7) 41.8 ± 4.6% wound closure; P < 0.001 vs Ang II). Furthermore, both peptides significantly inhibited FCS induced VSMC proliferation (P < 0.05). The inhibitory effects of Ang-(1–9) and Ang-(1–7) on VSMC migration and proliferation were selectively blocked by PD and A779, respectively, suggesting Ang-(1–9) acts via the AT2R and Ang-(1–7) via Mas. Neither Ang-(1–9) or Ang-(1–7) prevented EC migration or proliferation. In vivo wire injury of the mouse carotid artery induced significant NI formation at 28days (NI/media area (NI/MA) 0.80 ± 0.07 injured control vs 0.01 ± 0.01 sham; P < 0.001); this was attenuated by Ang-(1–9) (NI/MA 0.17 ± 0.1; P < 0.001 vs injured control) and Ang-(1–7) (NI/MA 0.40 ± 0.07; P < 0.05 vs injured control). The effects of Ang-(1–9) were blocked by PD (P < 0.001 vs Ang-(1–9) alone) while the effects of Ang-(1–7) were blocked by A779 (P < 0.05 vs Ang-(1–7) alone), suggesting that in vivo Ang-(1–9) acts via the AT2R and Ang-(1–7) acts via Mas.We demonstrate for a novel, direct effect of Ang-(1–9) in inhibiting VSMC proliferation and migration in vitro, and reducing neointimal formation in vivo via the AT2R. These data provide further insight into the role of the Ang-(1–9)/AT2R interaction in the vasculature and highlights the potential of Ang-(1–9) as a therapeutic agent for vascular remodelling.

Introduction Vascular smooth muscle cell (VSMC) migration is integral to vascular remodelling in acute vascular injury.