Loss of FoxO3a prevents aortic aneurysm formation through maintenance of VSMC homeostasis

Weiling Lu,Shan Zeng,Yiming Zhong,Gonghua Hu,Qin Liao,Shiju Zhou,Yalan Wang,Jiahe Xie,Haoyu Song,Rongming Ding,Lianglliang Lyu,Yuhua Hu,Gaojun Zhong,Qingrui Li,Yu Zhou,Lintao Zhong,Yulin Liao,Dongming Xie,Zhongyu Wen

doi:10.1038/s41419-021-03659-y

Abstract

Vascular smooth muscle cell (VSMC) phenotypic switching plays a critical role in the formation of abdominal aortic aneurysms (AAAs). FoxO3a is a key suppressor of VSMC homeostasis. We found that in human and animal AAA tissues, FoxO3a was upregulated, SM22α and α-smooth muscle actin (α-SMA) proteins were downregulated and synthetic phenotypic markers were upregulated, indicating that VSMC phenotypic switching occurred in these diseased tissues. In addition, in cultured VSMCs, significant enhancement of FoxO3a expression was found during angiotensin II (Ang II)-induced VSMC phenotypic switching. In vivo, FoxO3a overexpression in C57BL/6J mice treated with Ang II increased the formation of AAAs, whereas FoxO3a knockdown exerted an inhibitory effect on AAA formation in ApoE−/− mice infused with Ang II. Mechanistically, FoxO3a overexpression significantly inhibited the expression of differentiated smooth muscle cell (SMC) markers, activated autophagy, the essential repressor of VSMC homeostasis, and promoted AAA formation. Our study revealed that FoxO3a promotes VSMC phenotypic switching to accelerate AAA formation through the P62/LC3BII autophagy signaling pathway and that therapeutic approaches that decrease FoxO3a expression may prevent AAA formation.

Highlights

An abdominal aortic aneurysm (AAA) is defined as regional dilation of the aorta of >50% of the diameter of the normal adjacent aortic tissue or focal dilation of ≥3 cm compared to the diameter of the normal adjacent arterial segment[1,2,3]
We found that the protein levels of the contractile smooth muscle cell (SMC) markers SM-22α and α-smooth muscle actin (α-SMA) were significantly downregulated in AAA tissues compared to normal tissues, while extracellular matrix proteolytic enzyme 2 (MMP2), a synthetic phenotype marker, was significantly upregulated (p < 0.01; Fig. 1E, F)
SM22α expression was significantly lower (p < 0.01) in human AAA tissue than in adjacent nonaneurysmal tissue (Fig. 1G, H). These results are consistent with the finding that upregulation of FoxO3a expression is accompanied by phenotypic changes in Vascular smooth muscle cell (VSMC) in human AAA

Summary

Introduction

An abdominal aortic aneurysm (AAA) is defined as regional dilation of the aorta of >50% of the diameter of the normal adjacent aortic tissue or focal dilation of ≥3 cm compared to the diameter of the normal adjacent arterial segment[1,2,3]. The prevalence of AAAs increases with age and is 4 to 8% in men and 0.5% to 1.5% in women[4]. Patients with large aneurysms (aneurysms with a diameter of 5.0 to 5.5 cm) are at high risk for rupture and are recommended to undergo open or interventional repair[5]. AAAs smaller than 5.5 cm in diameter are termed “small AAAs”6. Lifestyle changes and close observation are recommended for patients with small aneurysms due to the lack of effective pharmacotherapy options[6]. Therapeutic targets for AAAs have long been sought; we aimed to elucidate the pathogenesis of the disease

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Conclusion