Abstract
AngII and TGF-β interact in development of thoracic and abdominal aortic diseases, although there are many facets of this interaction that have not been clearly defined. The aim of the present study was to determine the effects of TGF-β neutralization on AngII induced-aortic pathologies. Male C57BL/6J mice were administered with either a rabbit or mouse TGF-β neutralizing antibody and then infused with AngII. The rabbit TGF-β antibody modestly reduced serum TGF-β concentrations, with no significant enhancements to AngII-induced aneurysm or rupture. Administration of this rabbit TGF-β antibody in mice led to high serum titers against rabbit IgG that may have attenuated the neutralization. In contrast, a mouse TGF-β antibody (1D11) significantly increased rupture in both the ascending and suprarenal aortic regions, but only at doses that markedly decreased serum TGF-β concentrations. High doses of 1D11 antibody significantly increased AngII-induced ascending and suprarenal aortic dilatation. To determine whether TGF-β neutralization had effects in mice previously infused with AngII, the 1D11 antibody was injected into mice that had been infused with AngII for 28 days and were observed during continued infusion for a further 28 days. Despite near ablations of serum TGF-β concentrations, the mouse TGF-β antibody had no effect on aortic rupture or dimensions in either ascending or suprarenal region. These data provide further evidence that AngII-induced aortic rupture is enhanced greatly by TGF-β neutralization when initiated before pathogenesis.
Highlights
Aortic aneurysm is defined as a permanent dilation of the lumen and represents a potentially fatal condition due to its high risk for rupture [1]
To determine the effects of TGF-β neutralization on ascending and suprarenal aortic aneurysm formation, we injected either IgG control or polyclonal rabbit TGF-β antibodies, at a dose of 10 mg/kg twice per week, into C57BL/6J mice infused with AngII
Since platelets are a major source of TGF-β, they were measured in whole blood to determine whether the neutralizing antibody would have an effect on their population
Summary
Aortic aneurysm is defined as a permanent dilation of the lumen and represents a potentially fatal condition due to its high risk for rupture [1]. Aortic aneurysms are commonly located at specific regions within the thoracic and abdominal aorta. Effects of TGF-β Neutralization on Aortic Aneurysms aortic aneurysms have distinct clinical presentations and pathological features, an aberrant renin-angiotensin system (RAS) has been invoked in the pathogenesis of both regions [2]. This includes many studies demonstrating that AngII infusion promotes formation of aneurysm and rupture in both ascending and suprarenal aortic regions in mice [3,4,5,6,7,8,9]. Inhibition of AngII stimulation through either pharmacological antagonism of AT1 receptors or genetic disruption of AT1a receptors reduces both ascending and suprarenal aortic aneurysms in several animal models [8,10,11,12]
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