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Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8675-E8684. doi: 10.1073/pnas.1702223114. Epub 2017 Sep 25.

Autophagy is required for endothelial cell alignment and atheroprotection under physiological blood flow.

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INSERM, U970, Paris Cardiovascular Research Center, 75015 Paris, France.
Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
Université Paris Diderot, Sorbonne Paris Cité, 75013 Paris, France.
INSERM U1151, Institut Necker-Enfants Malades-INEM, 75014 Paris, France.
CNRS UMR 8253, 75014 Paris, France.
Medizinische Klinik I, Klinikum der Universität München, 81377 Munich, Germany.
Mechanics & Living Systems, Cardiovascular Cellular Engineering, Laboratoire d'Hydrodynamique, Ecole Polytechnique, UMR 7646, 91128 Palaiseau, France.
INSERM UMR_S1131/IHU/Université Paris Diderot, 75013 Paris, France.
INSERM U1016, Institut Cochin, 75014 Paris, France.
CNRS, UMR 8104, 75014 Paris, France.
Service de Chirurgie Cardiaque et Vasculaire, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France.
INSERM, U970, Paris Cardiovascular Research Center, 75015 Paris, France;
Département Hospitalo-Universitaire Unity, Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, Hôpital Beaujon, Assistance Publique-Hopitaux de Paris, 92110 Clichy, France.


It has been known for some time that atherosclerotic lesions preferentially develop in areas exposed to low SS and are characterized by a proinflammatory, apoptotic, and senescent endothelial phenotype. Conversely, areas exposed to high SS are protected from plaque development, but the mechanisms have remained elusive. Autophagy is a protective mechanism that allows recycling of defective organelles and proteins to maintain cellular homeostasis. We aimed to understand the role of endothelial autophagy in the atheroprotective effect of high SS. Atheroprotective high SS stimulated endothelial autophagic flux in human and murine arteries. On the contrary, endothelial cells exposed to atheroprone low SS were characterized by inefficient autophagy as a result of mammalian target of rapamycin (mTOR) activation, AMPKα inhibition, and blockade of the autophagic flux. In hypercholesterolemic mice, deficiency in endothelial autophagy increased plaque burden only in the atheroresistant areas exposed to high SS; plaque size was unchanged in atheroprone areas, in which endothelial autophagy flux is already blocked. In cultured cells and in transgenic mice, deficiency in endothelial autophagy was characterized by defects in endothelial alignment with flow direction, a hallmark of endothelial cell health. This effect was associated with an increase in endothelial apoptosis and senescence in high-SS regions. Deficiency in endothelial autophagy also increased TNF-α-induced inflammation under high-SS conditions and decreased expression of the antiinflammatory factor KLF-2. Altogether, these results show that adequate endothelial autophagic flux under high SS limits atherosclerotic plaque formation by preventing endothelial apoptosis, senescence, and inflammation.


atherosclerosis; autophagy; endothelial; inflammation; shear stress

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