4.8 Article

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

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1702223114

Keywords

endothelial; autophagy; shear stress; atherosclerosis; inflammation

Funding

  1. Institut National de la Sante et de la Recherche Medicale, Paris Descartes University
  2. Fondation pour la Recherche Medicale [DPC20111122979, FDT20160435690]
  3. Agence Nationale pour la Recherche [ANR-14-CE12-0011, ANR-14-CE35-0022, ANR-16-CE14-0015-01]
  4. Association Francaise pour l'Etude du foie Grant AFEF
  5. poste d'accueil INSERM
  6. Cardiovasculaire, Obesite, Diabete Domaine d'Interet Majeur Ile de France
  7. Ministere de la Recherche et de l'Enseignement Superieur
  8. Agence Nationale de la Recherche (ANR) [ANR-14-CE35-0022, ANR-16-CE14-0015] Funding Source: Agence Nationale de la Recherche (ANR)

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It has been known for some time that atherosclerotic lesions preferentially develop in areas exposed to lowSS 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, AMPKa 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-alpha-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.

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