PMC

Mechanism of protection by AT2 signaling. (A) Western blot analysis of ERK1/2 and Smad2 activation in the aortic root and proximal ascending aorta of four mice of each genotype. Note that Smad2 activation is increased equally in AT2KO:Fbn1^C1039G/+ and Fbn1^C1039G/+ mice, compared with WT littermates. ERK1/2 activation is significantly increased in Fbn1^C1039G/+ mice when compared with WT littermates and is further increased in AT2KO:Fbn1^C1039G/+ mice. (B) Western blot analysis of ERK1/2 and Smad2 activation in the aortic root and proximal ascending aortas of three each of WT and placebo-, losartan- or enalapril-treated Fbn1^C1039G/+ mice. Note that Smad2 activation is decreased in both losartan- and enalapril-treated Fbn1^C1039G/+ mice when compared with placebo-treated animals, with a more pronounced effect in enalapril-treated animals. In contrast, enalapril treatment failed to reduce ERK1/2 activation, whereas losartan reduced ERK1/2 activation to levels indistinguishable from WT littermates. (C) Western blot analysis of ERK1/2 activation in the aortic root and proximal ascending aorta of three WT, AT2KO, and placebo- or losartan-treated AT2KO:Fbn1^C1039G/+ mice. Note that losartan loses its ability to decrease ERK1/2 activation in AT2KO:Fbn1^C1039G/+ mice, demonstrating that the inhibition of ERK1/2 activation is mediated by the AT2 receptor. (D) Summary of the effects of AngII receptors on both canonical and noncanonical TGFβ signaling. AT1 receptor stimulation drives ERK1/2 activation, whereas AT2 receptor stimulation inhibits it. Losartan attenuates ERK1/2 activation by blocking the AT1 cascade while simultaneously shunting signaling through the AT2 receptor. *P <0.05; **P <0.01; †P < 0.001; NS, not significant.

Therapeutic effects in the aorta. (A) WT (n = 5), AT2KO (n = 4), Fbn1^C1039G/+ (n = 7), and AT2KO:Fbn1^C1039G/+ (n = 7) mice. Verhoeff–Van Gieson (VVG) stain reveals diffuse fragmentation of elastic fibers and thickening of the media in Fbn1^C1039G/+ mice; these findings are exaggerated in AT2KO:Fbn1^C1039G/+ mice. (B) Average aortic root growth (T2SEM) over 7 months of treatment in placebo- (n = 13) orlosartan- (n = 7) treated WT mice and placebo- (n = 17), losartan- (n = 5), or enalapril- (n = 15) treated Fbn1^C1039G/+ mice, as measured by echocardiography. Note the regression in aortic size observed in losartan-treated Fbn1^C1039G/+ mice and the marginal (P = 0.05) decrease in growth in the enalapril-treated cohort. Final absolute aortic root diameter: WT (1.74 ± 0.10 mm), losartan-treated WT (1.77 ± 0.15 mm), Fbn1^C1039G/+ (2.19 ± 0.19 mm), losartan-treated Fbn1^C1039G/+ (1.96 ± 0.09 mm), and enalapril-treated Fbn1^C1039G/+ (2.18 ± 0.18 mm). (C) Average aortic root growth (±2SEM) over 7 months of treatment in WT (n = 8), placebo- (n = 22), and losartan- (n = 11) treated Fbn1^C1039G/+ mice and placebo- (n = 19) and losartan- (n = 6) treated AT2KO:Fbn1^C1039G/+ mice. Note the diminished effectiveness of losartan treatment in AT2KO:Fbn1^C1039G/+ mice, as compared with losartan treatment in Fbn1^C1039G/+ mice. Final absolute aortic root diameter: WT (1.77 ± 0.10 mm), Fbn1^C1039G/+ (2.13 ± 0.16 mm), AT2KO:Fbn1^C1039G/+ (2.34 ± 0.13 mm), losartan-treated Fbn1^C1039G/+ (1.96 ± 0.09 mm), and losartan-treated AT2KO:Fbn1^C1039G/+ (2.06 ± 0.07 mm). *P < 0.05; **P < 0.01; †P < 0.001; ††P < 0.0001; NS, not significant.

The role of AngII in the aorta. (A) AngII acts on the AT1 receptor causing increased cellular proliferation, fibrosis, and matrix metalloproteinase–2and/or −9 (MMP2/9) activity while decreasing apoptosis. Conversely, the AT2 receptor is thought to decrease proliferation, fibrosis, and MMP activity, while increasing apoptosis. ACEi's block the conversion of AngI to AngII, limiting signaling through both AT1 and AT2 receptors, whereas ARBs selectively block AT1. (B) Average absolute aortic root diameter (±2SEM) measured serially by echo-cardiogram over the first year of life. Note that AT2KO:Fbn1^C1039G/+ mice have a significantly larger aortic root diameter than Fbn1^C1039G/+ mice at each time point. (C) Kaplan-Meier survival curve demonstrating an increased rate of death in AT2KO:Fbn1^C1039G/+ as compared with Fbn1^C1039G/+ mice. (D) Ascending aortic growth from 2 to 12 months of age. Note the increased rate of ascending aortic growth in AT2KO:Fbn1^C1039G/+ mice. Final absolute ascending aortic diameter: WT (1.41 ± 0.07 mm), AT2KO (1.40 ± 0.07 mm), Fbn1^C1039G/+ (1.42 ± 0.20 mm), AT2KO:Fbn1^C1039G/+ (1.72 ± 0.42 mm). (B to D) WT (n = 5), AT2KO (n =10), Fbn1^C1039G/+ (n =17), AT2KO:Fbn1^C1039G/+ (n =19). *P < 0.05; †P < 0.001; ††P < 0.0001; NS, not significant.