Defective autophagy in vascular smooth muscle cells increases passive stiffness of the mouse aortic vessel wall

Abstract

Aging and associated progressive arterial stiffening are both important predictors for the development of cardiovascular diseases. Recent evidence showed that autophagy, a catabolic cellular mechanism responsible for nutrient recycling, plays a major role in the physiology of vascular cells such as endothelial cells and vascular smooth muscle cells (VSMCs). Moreover, several autophagy inducing compounds are effective in treating arterial stiffness. Yet, a direct link between VSMC autophagy and arterial stiffness remains largely unidentified. Therefore, we investigated the effects of a VSMC-specific deletion of the essential autophagy-related gene Atg7 in young mice (3.5 months) (Atg7F/F SM22α-Cre+ mice) on the biomechanical properties of the aorta, using an in-house developed Rodent Oscillatory Tension Set-up to study Arterial Compliance (ROTSAC). Aortic segments of Atg7F/F SM22α-Cre+ mice displayed attenuated compliance and higher arterial stiffness, which was more evident at higher distention pressures. Passive aortic wall remodeling, rather than differences in VSMC tone, is responsible for these phenomena, since differences in compliance and stiffness between Atg7+/+ SM22α-Cre+ and Atg7F/F SM22α-Cre+ aortas were more pronounced when VSMCs were completely relaxed by the addition of exogenous nitric oxide. These observations are supported by histological data showing a 13% increase in medial wall thickness and a 14% decrease in elastin along with elevated elastin fragmentation. In addition, expression of the calcium-binding protein S100A4, which is linked to matrix remodeling, was elevated in aortic segments of Atg7F/F SM22α-Cre+ mice. Overall, these findings illustrate that autophagy exerts a crucial role in defining arterial wall compliance.

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Acknowledgments

The authors are grateful to Rita Van den Bossche, Hermine Fret, Nick Bakker, and Geoffrey De Laender for excellent technical support, and Dr. Bronwen Martin for critical reading of the manuscript.

Funding

This work was supported by the Fund for scientific Research (FWO)-Flanders (grant number G.0412.16 N), the Hercules Foundation (grant number AUHA/13/03), and the University of Antwerp (BOF). D.G. De Munck is a fellow of the FWO-Flanders.

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D.D.M., A.J.A.L, and P.F. conception and design of research. D.D.M. and P.F. performed experiments. D.D.M. analyzed data and D.D.M. and P.F. interpreted results of experiments. D.D.M prepared the figures and drafted the manuscript. D.D.M., G.R.Y.D.M, W.M., and P.F. edited and revised the manuscript. D.D.M, A.J.A.L, G.R.Y.D.M, W.M., and P.F. approved the final version of the manuscript.

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Correspondence to Paul Fransen.

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De Munck, D.G., Leloup, A.J., De Meyer, G.R.Y. et al. Defective autophagy in vascular smooth muscle cells increases passive stiffness of the mouse aortic vessel wall. Pflugers Arch - Eur J Physiol (2020). https://doi.org/10.1007/s00424-020-02408-y

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Keywords

  • Autophagy
  • Vascular smooth muscle cell
  • Arterial stiffness
  • Mouse aorta