Angiotensin 1-7 exerts protective effects in thoracic aortic aneurysm by attenuating smooth muscle cell phenotypic switching

Background: Thoracic aortic aneurysm (TAA) involves extracellular matrix (ECM) remodeling of the aortic wall, leading to reduced biomechanical support with risk of aortic dissection and rupture. Elusive pathophysiology of initiation and progression of TAA has hindered efforts to develop pharmacological therapeutic interventions to delay or prevent progressive aortic dilatation. Activation of the renin-angiotensin system, and resultant Angiotensin (Ang) II synthesis, is critically involved in the onset and progression of TAA. The current study investigated the effects of Angiotensin (Ang) 1-7 on a murine model of TAA. Methods & Results: 8-10 weeks old apolipoprotein-deficient mice (ApoEKO) were infused with Ang II (1.44 mg/kg/day) and treated with Ang 1-7 (0.576 mg/kg/day). Echocardiography and histological analyses revealed increased thoracic aortic dilatation, ECM remodeling, perivascular fibrosis, and inflammation in Ang II-treated mice. Infusion of Ang 1-7 led to suppression of Ang II-induced dilatation, remodeling, and inflammation in the thoracic aorta. The immunofluorescence imaging showed reduced α-SMA fluorescence (contractile marker) in vascular smooth muscle cells (VSMCs) of the aortic media indicating phenotypic switching. In response to Ang II, the thoracic VSMCs from ApoEKO mice exhibited phenotypic switching indicated by reduced contractile ( Acta2, Cnn1, Myh11 ) and increased synthetic ( Il-6, Mmp2, Mmp9, Col1a1, Col3a1 ) gene expression. Ki67 staining and flow cytometry analysis showed VSMCs hyperproliferation with Ang II treatment. Ang 1-7 preserved the contractile phenotype of VSMCs and attenuated hyperproliferation. The mitochondrial structure was assessed using MitoTracker Red staining which showed Ang II-induced excessive mitochondrial fission. DHE and MitoSOX Red staining were used to assess the reactive oxygen species (ROS). Ang II-treated thoracic VSMCs demonstrated elevated cellular and mitochondrial ROS generation. Ang 1-7 mitigated Ang II-induced mitochondrial fission and oxidative stress. Conclusion: Ang 1-7 prevented Ang II-induced vascular remodeling and the development of TAA. Enhancing Ang 1-7 actions may provide a novel therapeutic strategy to prevent or delay the progression of TAA.