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MitoVasc : physiopathologie cardiovasculaire et mitochondriale


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    Flow (shear stress)-mediated mechanotransduction in the endothelial cell and flow-mediated remodeling in vivo

    Flow (shear stress)-mediated mechanotransduction in the endothelial cell and flow-mediated remodeling in vivo

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    Daniel Henrion


    Team members : 

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

    Marie Briet, PUPH

    Anne-Laure Guihot, Assistant Engineer CNRS

    Emilie Vessières, Engineer, UA

    Linda Grimaud, Assistant-Engineer, UA

    Coralyne Proux, Engineer, CNRS (Mitoshear project)

    Jordan Rivron, Assistant-Engineer, UA and ANR (Estroshear project)

    Manuela Garcia, Engineer, UA and ANR (Sphipervasc project)

    Ahmad Chehaitly, Ph.D. student, (Mitoshear project)

     

    Beside large conductance arteries, arterioles, the small resistance arteries located upstream capillaries control blood delivery to tissues at relevant flow and pressure. Disorders in their structure and function can raise downstream capillary pressure, which induces organ damage, and can participate upstream to increased blood pressure and cardiovascular risk. The endothelium has a key role in the control of local blood flow by resistance arteries. Flow (shear stress) induces the production of vasodilators by endothelial cells leading to flow-mediated dilatation (FMD). Reduced FMD is the hallmark of endothelium dysfunction. FMD is altered early in ageing especially when associated with cardiometabolic risk factors. Women are protected against cardiovascular disorders compared to men. Nevertheless, a unique case of lack of ERα described in a man was associated with early atherosclerosis and a selective loss of FMD. We have shown that estradiol and endothelial estrogen receptor alpha (ERα) are involved in atheroprotection and flow-mediated outward remodeling (FMR, or collateral arteries growth in ischemic diseases). We also began to decipher the respective roles of classic nuclear, transcriptional ERα and of a more recently characterized extranuclear membrane ERα. We hypothesize that membrane ERα is an important actor of endothelial mechanotransduction (shear stress signaling) and propose to determine its role in the RAs homeostasis. This project is supported by the National Agency for Research (ANR).


    Besides the estrogen receptor, circulating and tissue lipids such as sphingosine-1-phosphate (S1P) are potent regulators of vascular homeostasis. S1P is an abundant plasma lipid that is carried on high-density lipoproteins (HDL) and that mediates in part their vascular protective functions through activation of G protein-coupled receptor signaling. S1P signaling is essential for the integrity of the cardiovascular system. A growing body of evidence suggests that S1P may sustain pressure-induced (myogenic) tone and mediate endothelial shear stress sensing and dilatation in resistance arteries. Using mouse lines engineered for temporal and spatial deficiency in S1P production and S1P receptors, we will address the potential of blood and vessel wall-derived S1P to modulate vascular function in isolated vessels and organs and in the intact organism. We expect finding how S1P signaling is engaged to regulate resistance artery function and blood pressure, and thus on the potential diagnostic value of blood S1P for microvascular health and the development of hypertension.


    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 team 1 (Mitolab) we 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:

    • Fondation pour la Recherche Médicale (2018-2020), MitoShear project (coord. Henrion).
    • ANR (2018-2021), Estroshear project (coord. D. Henrion, collab. with JF Arnal, Toulouse)
    • ANR (2020-2022), Sphipervasc project (Coord. E. Camerer, PARCC, Paris)

    Collaborations:

    • JF Arnal, Dr. F. Lenfant & Dr. C. Fontaine (I2CM, INSERM U1048, Toulouse) ; Estroshear project (ANR).
    • B. Lévy (PARCC, INSERM U970), Risk factors and neurovascular diseases.
    • M. Iglarz (Idorsia Pharmaceutical ltd, Basel, Switzerland). Risk factors and vascular aging.
    • E. Camerer (PARCC, INSERM U970), Sphipervasc project (ANR)
    • P. Bonnin (Service de Physiologie Clinique Explorations Fonctionnelles, INSERM U965, Hôpital Lariboisière), Sphipervasc project (ANR)
    • G. Osol (Univ. of Vermont, USA), Uterine artery remodeling
    • M. Mandala (Univ of Calabria, Italy), vascular remodeling in pregnancy
    • V. Nivet, UMR S-1140, Paris. Métabolisme et pathophysiologie cardiovasculaire.
    • G. Flouriot, Irset - Inserm UMR_S 1085, Pathophysiologie des récepteurs oetrogéniques.
    • Dr. Stefan Offermanns, Max Planck Institute for Heart and Lung Research Dept. of Pharmacology, Bad Nauheim, Germany. Mechanosensitve GPCRs and G-proteins.

     

    References:

    Review articles:
    • 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.
    • Mallat Z, Tedgui A, Henrion D. Role of Microvascular Tone and Extracellular Matrix Contraction in the Regulation of Interstitial Fluid: Implications for Aortic Dissection. Arterioscler Thromb Vasc Biol. 2016;36:1742-7.
    Research articles:

     

    • Chennupati R, Wirth A, Favre J, Li R, Bonnavion R, Jin YJ, Wietelmann A, Schweda F, Wettschureck N, Henrion D, Offermanns S. Myogenic vasoconstriction requires G12/G13 and LARG to maintain local and systemic vascular resistance. Elife. 2019 Sep 24;8. pii: e49374.
    • Omarjee L, Roy C, Leboeuf C, Favre J, Henrion D, Mahe G, Leftheriotis G, Martin L, Janin A, Kauffenstein G. Evidence of Cardiovascular Calcification and Fibrosis in Pseudoxanthoma Elasticum Mouse Models Subjected to DOCA-Salt Hypertension. Sci Rep. 2019 Nov 8;9(1):16327
    • Urbanski G, Caillon A, Poli C, Kauffenstein G, Begorre MA, Loufrani L, Henrion D, Belizna C. Hydroxychloroquine partially prevents endothelial dysfunction induced by anti-beta-2-GPI antibodies in an in vivo mouse model of antiphospholipid syndrome. PLoS One. 2018; 13(11):e0206814.
    • *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
    • 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.
    • 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. 
    • 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  Hypertens, 2011, 29:102-12.
    • 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.
    • 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.
    • 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.  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.
    • 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, Lévy BI, Henrion D. Defect in microvascular adaptation to chronic changes in blood flow in mdx mice.  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.