AUTHOR=Pothen Lucie , Verdoy Roxane , De Mulder Delphine , Esfahani Hrag , Farah Charlotte , Michel Lauriane Y. M. , Dei Zotti Flavia , Bearzatto Bertrand , Ambroise Jerome , Bouzin Caroline , Dessy Chantal , Balligand Jean-Luc 

TITLE=Sustained Downregulation of Vascular Smooth Muscle Acta2 After Transient Angiotensin II Infusion: A New Model of “Vascular Memory”

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.854361

DOI=10.3389/fcvm.2022.854361

ISSN=2297-055X

ABSTRACT=<sec><title>Background</title><p>Activation of the renin-angiotensin-aldosterone system (RAAS) plays a critical role in the development of hypertension. Published evidence on a putative “memory effect” of AngII on the vascular components is however scarce.</p></sec><sec><title>Aim</title><p>To evaluate the long-term effects of transient exposure to AngII on the mouse heart and the arterial tissue.</p></sec><sec><title>Methods</title><p>Blood pressure, cardiovascular tissue damage and remodeling, and systemic oxidative stress were evaluated in C57/B6/J mice at the end of a 2-week AngII infusion (<italic>AngII</italic>); 2 and 3 weeks after the interruption of a 2-week AngII treatment (<italic>AngII</italic>+<italic>2W</italic> and <italic>AngII</italic> +<italic>3W</italic>; so-called “memory” conditions) and control littermate (<italic>CTRL</italic>). RNAseq profiling of aortic tissues was used to identify potential key regulated genes accounting for legacy effects on the vascular phenotype. RNAseq results were validated by RT-qPCR and immunohistochemistry in a reproduction cohort of mice. Key findings were reproduced in a homotypic cell culture model.</p></sec><sec><title>Results</title><p>The 2 weeks AngII infusion induced cardiac hypertrophy and aortic damage that persisted beyond AngII interruption and despite blood pressure normalization, with a sustained vascular expression of ICAM1, infiltration by CD45+ cells, and cell proliferation associated with systemic oxidative stress. RNAseq profiling in aortic tissue identified robust <italic>Acta2</italic> downregulation at transcript and protein levels (α-smooth muscle actin) that was maintained beyond interruption of AngII treatment. Among regulators of <italic>Acta2</italic> expression, the transcription factor Myocardin (<italic>Myocd</italic>), exhibited a similar expression pattern. The sustained downregulation of <italic>Acta2</italic> and <italic>Myocd</italic> was associated with an increase in H3K27me3 in nuclei of aortic sections from mice in the “memory” conditions. A sustained downregulation of <italic>ACTA2</italic> and <italic>MYOCD</italic> was reproduced in the cultured human aortic vascular smooth muscle cells upon transient exposure to Ang II.</p></sec><sec><title>Conclusion</title><p>A transient exposure to Ang II produces prolonged vascular remodeling with robust <italic>ACTA2</italic> downregulation, associated with epigenetic imprinting supporting a “memory” effect despite stimulus withdrawal.</p></sec>