Deletion of ACTA2 in mice promotes angiotensin II induced pathogenesis of thoracic aortic aneurysms and dissections.

Background: Mutation of the ACTA2 (α-2 smooth muscle actin) gene accounts for ~15% of all cases of familial thoracic aortic aneurysms and dissections. Surprisingly, no severe vascular phenotypes were observed at baseline in mice carrying this gene mutation. Our aim was to explore whether mutation of ACTA2 promotes the development of aneurysms or dissections in the presence of angiotensin II (AngII) and to determine whether this mutation has an impact on the phenotypic modulation and apoptosis mediated by AngII in vascular smooth muscle cells (VSMCs).

Methods: Mice were divided into three groups: AngII stimulated-wild-type (WT) (AngII) and ACTA2 mice (ACTA2) group, in which AngII were administered subcutaneously into 8-week-old C57 mice and ACTA2 mice, respectively, for 4 weeks using osmotic minipumps, and the control group (WT), in which the WT mice were infused with normal saline (NS). Ultrasound was performed to quantify lumen diameters. RT-qPCR and Western blot were used to assess gene expression, and histobiochemistry was used to evaluate the pathological changes in the thoracoabdominal aortas. TUNEL was used to assess apoptosis in VSMCs.

Results: Compared with the AngII- group, the ACTA2 mice exhibited more severity of dilated lumena of the aortas, a significantly increased expression of osteopontin (OPN), an elevated ratio of Bax/Bcl-2, increased apoptosis, and a decreased expression of α-smooth muscle actin (α-SMA).

Conclusions: Knockout of ACTA2 promoted AngII induced progressive lumen dilation of the aortas, apoptosis, and the phenotypic modulation in VSMCs in mice.