Endothelial Physiopathology and Extracellular Vesicles – Feb. 2021 CFATG
Endothelial Physiopathology and Extracellular Vesicles – Feb. 2021

Team: Endothelial Physiopathology and Extracellular Vesicles

Paris Centre de Recherche Cardiovasculaire, Hôpital Européen Georges Pompidou
Adresse : 56 rue Leblanc, 75015, Paris, France
Tel : +33 1 53 98 80 86

Team presentation

Web site: http://parcc.inserm.fr/research-teams/team/boulanger/
Team Leader : Chantal M. Boulanger, Inserm Research Director, chantal.boulanger@inserm.fr
Team members
Xavier Loyer, Researcher
Olivier Blanc-Brude, Researcher
Dominique Charue, Engineer
Cecile Devue, Engineer
Fariza Mezine, Engineer
Michaël Robillard, Engineer
Pierre-Michaël Coly, Postdoc
Shruti Chatterjee, Postdoc
Stephane Mazlan, Postdoc
Pierre Julia, Clinician
Sylvain Lejeune, Clinician
Nicolas Amabile, Clinician

From left to right: (Top) Alice Algans, Pierre-Michaël Coly, Xavier Loyer ; (Middle) Juliette Lasselin, Jules Merian, Anis Khiat, Dominique Charue, Rana Atfeh, Marie Le Hoang, Pierre-Emmanuel Rautou, Stephane Mazlan, Michaël Robillard, Shruti Chatterjee ; (Bottom) Olivier Blanc-Brude, Chantal Boulanger, Marion Tanguy, Johanne Poisson, Cécile Devue, Adel Hammoutene

Key words : Autophagy, endothelium, atherosclerosis, nonalcoholic steatohepatitis, extracellular vesicles

Research focus
Our work is focused on the role of autophagy in endothelial cells and its involvement in the pathophysiology of diseases related to metabolic syndrome (combination of obesity, insulin resistance or type 2 diabetes, dyslipidemia and hypertension).

Atherosclerosis is the arterial consequence of metabolic syndrome. It is an inflammatory disease of large arteries which preferentially develops in specific areas of the vasculature, where the blood flow is disturbed and exerts low shear stress, such as arterial bifurcations and curvatures. Conversely, areas exposed to high shear stress are protected from plaque development. We demonstrated that autophagy is activated in high shear stress areas and protects against atherosclerotic plaque formation (Fig. 1; Vion, Kheloufi et al., PNAS 2017). Conversely, autophagic flux is blocked in atheroprone low shear stress areas. This defect is responsible for the preferential plaque formation in atheroprone low shear stress areas, by inducing an endothelial inflammatory, apoptotic, and senescent phenotype. Currently, we are investigating how stimulating endothelial autophagy in atheroprone areas may impact endothelial inflammation and atherosclerotic plaque formation. As the microtubule network is an essential actor in the formation and turnover of autophagosomes, we are testing a strategy of microtubule stabilization, via α-tubulin acetylation, to restore adequate autophagic flux.

Figure 1: Under high laminar shear stress, endothelial autophagy is strongly induced and plays an anti-apoptotic, anti-senescent, anti-inflammatory, and antiatherogenic role. Under low shear stress, a defect in endothelial autophagy occurs as a result of an inhibition of the AMPKα and activation of the mTOR pathways together with a blockade of the fusion between autophagosomes with lysosomes. This defect in endothelial autophagy leads to endothelial apoptosis, senescence, and inflammation, eventually increasing atherosclerosis development. ICAM-1, intercellular adhesion molecule 1; KLF-2, Krüppel-like factor 2; MCP-1, monocyte chemoattractant protein 1. Solid lines indicate up-regulated pathways. Dashed lines indicate down-regulated pathways (Vion, Kheloufi et al., PNAS 2017).

Nonalcoholic fatty liver disease is the liver manifestation of the metabolic syndrome. It encompasses a spectrum of histological lesions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which includes, in addition to steatosis, hepatocellular injury, inflammation, and varying degree of fibrosis, and can progress to cirrhosis and liver cancer. We recently demonstrated that autophagy is defective in liver endothelial cells of patients with NASH and that this defect is induced by inflammatory mediators present in the portal blood of patients with metabolic syndrome (Fig. 2). We also demonstrated that deficiency in autophagy induces liver endothelial cell alterations responsible for liver inflammation, cell death and fibrosis, thus promoting NASH development (Hammoutene et al., J. Hepatol 2019). Our work demonstrates that autophagy is a key process involved in endothelial cell homeostasis in a metabolic syndrome setting in different vascular beds. Targeting endothelial autophagy is therefore an attractive strategy for the management of metabolic syndrome related disorders.

Figure 2: Autophagy is defective in the liver endothelial cells of patients with non-alcoholic steatohepatitis. This defect promotes liver inflammation and fibrosis at early stages of non-alcoholic steatohepatitis, but also at advanced stages of chronic liver disease (Hammoutene et al., 2018 J Hepatol).
Additionally, our team has pioneered research on the release of extracellular vesicles (apoptotic bodies, microvesicles or exosomes) from dysfunctional endothelial cells. These are lipid bilayer particles which enclose soluble cytosolic material originating from different subcellular compartments. We tested the hypothesis that specific changes in circulating extracellular vesicles represent a signature of vascular dysfunction and that vesicle content determines their functional effects during disease progression. We previously observed an increased release of endothelial microvesicles in atheroprone conditions, mimicked by in vitro low shear stress (Vion et al., Circ Res 2013). We are currently exploring the role of the autophagic process in the biogenesis of extracellular vesicles. The defect in autophagic flux, observed under atherorone conditions, may alter the content and function of endothelial extracellular vesicles. Early data indicate that inhibiting endothelial autophagy could lead to an enrichment in adhesion proteins and mitochondrial components, which could then impact the fate and function of these vesicles. Circulating vesicles may therefore contain potentially valuable biological information for biomarker discovery.

Key publications :
Anne-Clémence Vion, Bhama Ramkhelawon, Xavier Loyer, Gilles Chironi, Cecile Devue, Gervaise Loirand, Alain Tedgui, Stéphanie Lehoux, Chantal M Boulanger. Shear stress regulates endothelial microparticle release. Circ Res 2013, 112(10):1323-1333.

Anne-Clemence Vion*, Marouane Kheloufi*, Adel Hammoutene, Johanne Poisson, Juliette Lasselin, Cecile Devue, Isabelle Pic, Nicolas Dupont, Johanna Busse, Konstantin Stark, Julie Lafaurie-Janvore, Abdul I Barakat, Xavier Loyer, Michele Souyri, Benoit Viollet, Pierre Julia, Alain Tedgui, Patrice Codogno, Chantal M Boulanger# and Pierre-Emmanuel Rautou#. Autophagy is required for endothelial cell alignment and atheroprotection under physiological blood flow. Proc Natl Acad Sci USA 2017, 114(41):E8675-E8684. (* and #: equally contributed to the work)

Marouane Kheloufi, Anne-Clemence Viona, Adel Hammoutene, Johanne Poisson, Juliette Lasselin, Cecile Devue, Isabelle Pic, Nicolas Dupont, Johanna Busse, Konstantin Stark, Julie Lafaurie-Janvore, Abdul I. Barakat, Xavier Loyer, Michele Souyri, Benoit Viollet, Pierre Julia, Alain Tedgui, Patrice Codogno, Chantal M. Boulanger and Pierre-Emmanuel Rautou. Endothelial autophagic flux hampers atherosclerotic lesion development. Autophagy 2018, 14(1):173–175.

Adel Hammoutene, Louise Biquard, Juliette Lasselin, Marouane Kheloufi, Marion Tanguy, Anne-Clémence Vion, Jules Mérian, Nathalie Colnot, Xavier Loyer, Alain Tedgui, Patrice Codogno, Sophie Lotersztajn, Valérie Paradis, Chantal M Boulanger and Pierre-Emmanuel Rautou. A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis. J Hepatol 2020, 72(3):528-538.

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