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    Flow (shear stress)-mediated remodeling: influence of aging and gender

    Flow (shear stress)-mediated remodeling: influence of aging and gender

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    Daniel Henrion and Vincent Procaccio

    Team members : 

    Daniel Henrion, Pharm.D., Ph.D. DR1 INSERM

    Vincent Procaccio, M.D., Ph.D., PUPH

    Coralyne Proux, Engineer FRM - CNRS

    Linda Grimaud, assistant-engineer UA

    Anne-laure Guihot, assistant-engineer CNRS

    Jordan Rivron, assistant-engineer ANR - UA

    Yoan Moreau, technician - INSERM

    Ahmad Chehaitly,PhD student


    Chronic changes in blood flow (shear stress) occur in physiological (growth, pregnancy, exercise) and pathological conditions (post-ischemic revascularization). Changes in flow induce a remodeling aimed at normalizing wall shear stress. This remodeling requires an initial inflammatory response, oxidative stress and the production of NO. Peroxynitrite activate MMPs and matrix degradation.  

    We have shown that this remodeling does not occur in aging although this defect is reversible using a vasodilator treatment. We are now investigating flow-mediated remodeling in resistance arteries in aging in association with obesity and diabetes, which are more currently occurring in older subjects, and, in addition, the frequency of these disorders is dramatically increasing worldwide. 

    We have discovered that high-flow remodeling decreases with age in male rats and is absent after 12 months. High-flow remodeling is absent in young diabetic rats but preserved in obese 12-month-old rats due to the production of COX-2-derivared prostacycline. Nevertheless, in both diabetic and obese rats, endothelium (NO)-mediated dilation decreases in arteries submitted chronically to high blood flow instead of increasing as seen in healthy animals. In diabetic rats, the activation of MMPs by peroxinitrites is severely reduced, thus preventing digestion of the extracellular matrix and consequently diameter expansion. Nevertheless, a chronic treatment with the AGEs breaker ALT711 restored high flow-mediated remodeling and, in part, endothelium-mediated dilation. The effect of diabetes on high-flow-mediated remodeling in depicted below.

    We have shown that estrogens preserve flow-mediated remodeling in old rats. Indeed, uterine arteries have been shown to undergo rapid and extensive remodeling during each cycle and during pregnancy. Estradiol also plays a key role in endothelial repair after injury. In addition, women are better protected from cardiovascular diseases, an advantage lost after menopause. Our recent findings show that the endothelial estrogen receptor alpha (ERalpha) plays a key role in flow-mediated outward remodeling of small resistance arteries and that this effect is lost after a prolonged ovariectomy. Indeed, maintaining flow-mediated outward remodeling in women could be essential for a better drug management. Antihypertensive treatments might be more efficient with fewer medications thus minimizing the side effects, which remain important with multi-drug therapies. We now investigate the role of ERalpha in flow-mediated dilation, the acute vasodilatory response to flow (Estroshear project).

    Recent studies have shown the presence of estrogen receptors in mitochondria and suggested that estradiol alters mitochondrial function. We have demonstrated that in vivo estrogen replacement at physiological doses leads to increased levels of key mitochondrial proteins, such as cytochrome C, mitochondrial transcription factors and antioxidant enzymes, in cerebral blood vessels of ovariectomized female rats. Estrogens are potent regulator of mitochondria biogenesis and several recent studies suggest a role for the mitochondria in flow-mediated signaling. Taking advantage of the expertise of our team 1 (Mitolab) we now investigate the role of mitochondria dynamics in the response to shear stress of endothelial cells (Mitoshear project supported by the “Fondation pour la Recherche Médicale”.


    Project supported 

    -        by the “Fondation de France” (FDF, 2011-2013)

    -        Fondation pour la Recherche Médicale (2018-2020), MitoShear project

    -        ANR (2018-2021), Estroshear project (coord. D. Henrion, collab. With JF Arnal, Toulouse)


    -        Pr. JF Arnal (I2CM, INSERM U1048, Toulouse) ; Estroshear project

    -        Pr. B. Lévy (PARCC, INSERM U970), Risk factors and vascular aging.

    -        D. M. Iglarz  (Idorsia Pharmaceuticalltd, Basel, Switzerland). Risk factors and vascular aging.

    -        Pr S Duckles and Pr D Krause (University of California, Irvine)

    -        Pr. G. Osol (Univ. of Vermont, USA), Uterin artery remodeling

    -        Pr. M. Mandala (Univ  of Calabria, Italy), vascular remodeling in pregnancy

    Review article:

    Arnal JF, Lenfant F, Metivier R, Flouriot G, Henrion D, Adlanmerini M, Fontaine C, Gourdy P, Chambon P, Katzenellenbogen B, Katzenellenbogen J. Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications. Physiol Rev. 2017;97:1045-1087.


    • *Guivarc'h E, *Buscato M, Guihot AL, Favre J, Vessières E, Grimaud L, Wakim J, Melhem NJ, Zahreddine R, Adlanmerini M, Loufrani L, Knauf C, Katzenellenbogen JA, Katzenellenbogen BS, Foidart JM, Gourdy P, Lenfant F, Arnal JF, *Henrion D, *Fontaine C. Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety. J Am Heart Assoc. 2018 Jun 29;7(13). pii: e008950.     *equal contribution
    • Frey S, Geffroy G, Desquiret-Dumas V, Gueguen N, Bris C, Belal S, Amati-Bonneau P, Chevrollier A, Barth M, Henrion D, Lenaers G, Bonneau D, Reynier P, Procaccio V. The addition of ketone bodies alleviates mitochondrial dysfunction by restoring complex I assembly in a MELAS cellular model. Biochim Biophys Acta. 2017 ;1863(1):284-291.
    • Begorre MA, Dib A, Habchi K, Guihot AL, Bourreau J, Vessieres E, Blondeau B, Loufrani L, Chabbert M, Henrion D*, Fassot C. Microvascular vasodilator properties of the angiotensin II type 2 receptor in a mouse model of type 1 diabetes. Sci Rep. 2017 Mar 31;7:45625. doi: 10.1038/srep45625. *Corresponding author
    • Chenu C, Adlanmerini M, Boudou F, Chantalat E, Guihot AL, Toutain C, Raymond-Letron I, Vicendo P, Gadeau AP, Henrion D, Arnal JF, Lenfant F. Testosterone Prevents Cutaneous Ischemia and Necrosis in Males Through Complementary Estrogenic and Androgenic Actions. Arterioscler Thromb Vasc Biol. 2017 Mar 30.
    • Petit M, Guihot AL, Grimaud L, Vessieres E, Toutain B, Menet MC, Nivet-Antoine V, Arnal JF, Loufrani L, Procaccio V, Henrion D. Resveratrol Improved Flow-Mediated Outward Arterial Remodeling in Ovariectomized Rats with Hypertrophic Effect at High Dose. PLoS One. 2016 Jan 6;11(1):e0146148.
    • Gueguen N, Desquiret-Dumas V, Leman G, Chupin S, Baron S, Nivet-Antoine V, Vessières E, Ayer A, Henrion D, Lenaers G, Reynier P, Procaccio V. Resveratrol Directly Binds to Mitochondrial Complex I and Increases Oxidative Stress in Brain Mitochondria of Aged Mice. PLoS One. 2015 Dec 18;10(12):e0144290. 
    • Tarhouni K, Guihot AL, Vessieres E, Procaccio V, Grimaud L, Abraham P, Lenfant F, Arnal JF, Favre J, Loufrani L, Henrion D. Estrogens are needed for the improvement in endothelium-mediated dilation induced by a chronic increase in blood flow in rat mesenteric arteries. Vascul Pharmacol. 2016 ; 80:35-42.
    • Bedarida T, Baron S, Vibert F, Ayer A, Henrion D, Thioulouse E, Marchiol C, Beaudeux JL, Cottart CH, Nivet-Antoine V. Resveratrol Decreases TXNIP mRNA and Protein Nuclear Expressions With an Arterial Function Improvement in Old Mice. J Gerontol A Biol Sci Med Sci. 2015 Jun 3. pii: glv071.
    • Abot A, Fontaine C, Buscato M, Solinhac R, Flouriot G, Fabre A, Drougard A, Rajan S, Laine M, Milon A, Muller I, Henrion D, Adlanmerini M, Valéra MC, Gompel A, Gerard C, Péqueux C, Mestdagt M, Raymond-Letron I, Knauf C, Ferriere F, Valet P, Gourdy P, Katzenellenbogen BS, Katzenellenbogen JA, Lenfant F, Greene GL, Foidart JM, Arnal JF. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation. EMBO Mol Med. 2014;6:1328-46
    • Tarhouni K, Freidja ML, Guihot AL, Vessieres E, Grimaud L, Toutain B, Lenfant F, Arnal JF, Loufrani L, Henrion D. Role of estrogens and age in flow-mediated outward remodeling of rat mesenteric resistance arteries. Am J Physiol Heart Circ Physiol. 2014 ; 307, H504-H514
    • Tarhouni K, A.L. Guihot, E. Vessières, B. Toutain, V. Procaccio, L Grimaud, L. Loufrani, F. Lenfant, JF. Arnal, D. Henrion. Determinants of flow-mediated outward remodeling in female rodents: respective roles of age, estrogens and timing. Arterioscler Thromb Vasc Biol. 2014 ;34:1281-9.
    • Adlanmerini M, Solinhac R, Abot A, Fabre A, Raymond-Letron I, Guihot AL, Boudou F, Sautier L, Vessières E, Kim SH, Lière P, Fontaine C, Krust A, Chambon P, Katzenellenbogen JA, Gourdy P, Shaul PW, Henrion D, Arnal JF, Lenfant F. Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue-specific roles for membrane versus nuclear actions. Proc Natl Acad Sci U S A. 2014;111:E283-90.
    • Freidja ML, Vessieres E, Toutain B, Guihot AL, Custaud MA, Loufrani L, Fassot C, Henrion D. AGEs breaking and antioxidant treatment improves endothelium-dependent dilation without effect on flow-mediated remodeling of resistance arteries in old Zucker diabetic rats. Cardiovascular Diabetology, 2014;13:55. 
    • Vessieres E, Belin de Chantemèle EJ, Toutain B, Guihot AL, Jardel A, Loufrani L, Henrion D. COX-2-derived prostanoids and oxidative stress additionally reduce endothelium-mediated relaxation in old type 2 diabetic rats. PLOS One, 8(7):e68217.
    • Vessieres E, Belin de Chantemèle EJ, Toutain B, Guihot AL, Jardel A, Loufrani L, Henrion D. Cyclooxygenase-2-derived prostanoids reduce inward arterial remodeling induced by blood flow reduction in old obese Zucker rat mesenteric arteries. Vasc. Pharmacol. 2013 ; 58:356-62. 
    • Tarhouni K, Guihot AL, Freidja ML, Toutain B, Henrion B, Baufreton C, Pinaud F, Procaccio V, Grimaud L, Ayer A, Loufrani L, Lenfant F, Arnal JF, Henrion D. Key Role of Estrogens and Endothelial Estrogen Receptor α in Blood Flow-Mediated Remodeling of Resistance Arteries. Arterioscler Thromb Vasc Biol. 2013;33:605-11.
    • Freidja ML, Tarhouni K, Toutain B, Fassot-Lucht C, Loufrani L, Henrion D. The AGE-Breaker ALT-711 Restores High Blood Flow-Dependent Remodeling in Mesenteric Resistance Arteries in a Rat Model of Type 2 Diabetes. Diabetes. 2012 61:1562-72.
    • Freidja ML, Toutain B, Caillon A, Desquiret V, Lambert D, Loufrani L, Procaccio V, Henrion D. Heme Oxygenase 1 Is Differentially Involved in Blood Flow-Dependent Arterial Remodeling: Role of Inflammation, Oxidative Stress, and Nitric Oxide. Hypertension. 2011, 58:225-31.
    • Freidja ML, Vessières E, Desquiret V, Guihot AL, Toutain B, Jardel A, Procaccio V, Henrion D. Heme oxygenase-1 induction restores high-blood-flow-dependent remodelling and endothelial function in mesentericarteries of old rats J. Hypertens, 2011, 29:102-12.
    • Cousin M, Custaud MA, Baron-Menguy C, Toutain B, Dumont O, Guihot AL, Vessières E, Subra JF, Henrion D, Loufrani L, Role of Angiotensin II in the Remodeling Induced by a Chronic Increase in Flow in Rat Mesenteric Resistance Arteries. Hypertension, 2010;55:109-15.
    • Retailleau  K, Belin De Chantemele EJ, Vessieres E, Dumont O, Guihot AL, Toutain B, Henrion D, Loufrani L. Reactive oxygen species and cyclooxygenase-2-derived thromboxane A2 reduce AT2R vasorelaxation in diabetic rat resistance arteries, Hypertension, 2010;55:339-44.
    • Belin de Chantemele EJ, Vessieres E, Guihot AL, Toutain B, Loufrani L, Henrion D. Cyclooxygenase-2 preserves flow-mediated remodelling in old obese Zucker rat mesenteric arteries. Cardiovasc Res. 2010;81:788-96.
    • Baron-Menguy C, Toutain B, Cousin M, Dumont O, AL, Vessières E, Subra JF, Custaud MA, Loufrani L, Henrion D. Involvement of angiotensin II in the remodeling induced by a chronic decrease in blood flow in rat mesenteric resistance arteries. Hypertens. Res. 2010; 33:857-66.
    • Vessieres E, Belin de Chantemèle EJ, Toutain B, Guihot AL, Jardel A, Loufrani L, Henrion D. Cyclooxygenase-2 inhibition restored endothelium-mediated relaxation in old obese Zucker rat mesenteric arteries.  Front Physiol. 2010 Nov 2;1:145.
    • Belin de Chantemèle EJ, Vessières E, Guihot AL, Toutain B, Maquignau M, Loufrani L, Henrion D.Type 2 diabetes severely impairs structural and functional adaptation of rat resistance arteries to chronic changes in blood flow. Cardiovasc Res. 2009;81:788-96.
    • Belin De Chantemele EJ, Vessieres E, Dumont O, Guihot AL, Toutain B, Loufrani L, Henrion D. Reactive Oxygen Species Are Necessary for High Flow (Shear Stress)-induced Diameter Enlargement of Rat Resistance Arteries. Microcirculation. 2009;16:391-402.
    • Dumont O, Pinaud F, Guihot AL, Baufreton C, Loufrani L, Henrion D. Alteration in flow (shear stress)-induced structural and functional remodeling in rat resistance arteries with aging: improvement by a treatment with hydralazine. Cardiovasc. Res. 2008;77:600-608.
    • Dumont O, Loufrani L, Henrion D. Key role of the NO-pathway and MMP-9 in high blood flow-induced remodeling of rat resistance arteries. Arterioscler Thromb Vasc Biol. 2007, 27:317-324.
    • Bouvet C, Belin de Chantemèle E, Guihot AL, Vessières E, Bocquet A, Dumont O, Jardel A, Loufrani L, Moreau P, Henrion D. Flow-induced remodeling in resistance arteries from obese Zucker rats is associated with endothelial dysfunction. Hypertension 2007;50:248-54.
    • Celine Baron-Menguy, Arnaud Bocquet, Anne-Laure Guihot, Daniel Chappard, Ramaroson Andriantsitohaina, Laurent Loufrani, Daniel Henrion. Effects of red wine polyphenols on post-ischemic neovascularization model in rats: low doses are pro-angiogenic, high doses anti-angiogenic.  FASEB J.  2007 21:3511-21.
    • You D, Loufrani L, Baron C, Levy BI, Widdop R, Henrion D. High blood pressure reduction reverses AT2 receptor mediated vasoconstriction into vasodilation in spontaneously hypertensive rats. Circulation, 2005;111:1006-1011.
    • Loufrani L, Matrougui K, Li Z, Lévy BI, Lacolley P, Paulin D, Henrion D. Selective microvascular dysfunction in mice lacking the gene encoding for Desmin. FASEB J. 2002;16:117-119.
    • Loufrani L, Li Z,  Lévy BI, Paulin D, Henrion D. Excessive Microvascular Adaptation to Chronic Changes in Blood Flow in Mice Lacking the Gene Encoding for Desmin. Arterioscl Thromb Vasc Biol  2002; 22:1579-1584.
    • Loufrani L, Lévy BI, Henrion D. Defect in microvascular adaptation to chronic changes in blood flow in mdx mice. Circ. Res. 2002;91:1183-1189.
    • Loufrani L, Matrougui K, Gorny D, Duriez M, Blanc I, Lévy BI, Henrion D. Flow (shear stress)-induced endothelium-dependent dilation is altered in mice lacking the gene encoding for dystrophin. Circulation 2001; 103:864-870.