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    Vascular mechanotransduction; role of the local neuroeffector systems

    Vascular mechanotransduction; role of the local neuroeffector systems

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    Daniel Henrion

    Team members : 

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

    Cristina Belizna, M.D., Ph.D. MCU-PH

    Marie Briet, M.D., Ph.D. PUPH

    Emilie Vessières, Engineer UA

    Anne-Sophie Garnier, CCA, CHU Angers


    Besides the activation of extracellular matrix element and cytoskeletal scaffoldings, flow (shear stress) and pressure (myogenic tone)-dependent mechanotransduction involves neuro-hormonal systems. Among these local mediators, the renin-angiotensin and purinergic systems are more specifically in the scope of the laboratory. We have demonstrated the role of a balance between angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R) in the regulation of flow mediated dilation (FMD). AT1R stimulation reduces FMD, especially in hypertension whereas AT2R stimulation induces dilation. Nevertheless, in aging, hypertension and diabetes AT2R stimulation induces contraction. This alteration is, at least in part, associated with a vascular inflammatory response. Indeed, in diabetic rats we have shown that ThromboxaneA2 produced by COX2 reduces AT2R-mediated dilation.

    We currently investigate the role of inflammation in AT2R-dependent tone using models of chronic microvascular inflammation induced by anti-phospholipid antibodies (Cristina Belizna). Antiphospholipid syndrome is characterized by a recurrence of clinical events despite anticoagulation, and new therapies with anti-inflammatory effect or AT2R dependent could have a potential interest in this disease. Regarding purinergic receptors, we recently found that mice deficient for the major vascular extracellular nucleotides metabolizing enzyme (CD39/NTPDase1) present an exacerbated myogenic tone suggesting a participation of released nucleotides by vascular smooth muscle cells. The endothelium also is known to release large amounts of ATP in response to shear. Although the modalities of this release are not fully understood, the synergistic effect of ATP on intracellular calcium mobilization is evident. We hypothesize that the modulation of nucleotide P2 receptors participates in an autocrine mode in the cellular processes leading to acute and chronic adaptation of resistance arteries to mechanical strains. Using pharmacological approach and gene targeted animals, we focus our research on the identification of nucleotides release modalities and P2 receptors involved.

    The interaction between local and circulating systems affecting blood flow regulation through the modulation of FMD led us to investigate other systems such as the S1P1-dependent pathway and the pathways involved in autophagy.



    -        Dr. E. Camerer (PARCC, INSERM U970), Role of S1P in flow-mediated tone.

    -        Dr. P.L. Tharaux (PARCC, INSERM U970), autophagy and flow-mediated  tone

    -        Dr. JF Quignard (INSERM U1045, Bordeaux), Pulmonary disorders.

    -        Pr. A. Patapoutian (Scripps Institute, San Diego, USA), mechanosensitive channels


    Relevant Publications :

    • Belizna C, Stojanovitch L, Tervaert JWC, Fassot C, Henrion D, Loufrani L, Nagy G, Muchardt C, Hasan M, Ungeheuer MN, Arnaud L, Reig JA, Valverde EE, Nicoletti F, Saulnier P, Godon A, Reynier P, Chrétien JM, Damian L, Omarjee L, Mahé G, Pistorius MA, Meroni PL, Devreese K. Primary antiphospholipid syndrome and antiphospholipid syndrome associated to systemic lupus: Are they different entities? Autoimmun Rev. 2018. pii: S1568-9972(18)30138-1.
    • Merkulova-Rainon T, Mantsounga CS, Broquères-You D, Pinto C, Vilar J, Cifuentes D, Bonnin P, Kubis N, Henrion D, Silvestre JS, Lévy BI. Peripheral post-ischemic vascular repair is impaired in a murine model of Alzheimer's disease. Angiogenesis. 2018.
    • Dib A, Payen C, Bourreau J, Munier M, Grimaud L, Fajloun Z, Loufrani L, Henrion D, Fassot C. In Utero Exposure to Maternal Diabetes Is Associated With Early Abnormal Vascular Structure in Offspring. Front Physiol. 2018;9:350.
    • Xu J, MathurJ, VessièresV, HammackS, NonomuraK, FavreJ, Grimaud L, PetrusM, FranciscoA, LiJ, LeeV, XiangFL, MainquistJK, CahalanSM, OrthAP, WalkerJR, MaS, LukacsV, BandellM, BordoneL, LaffitteB, XuY, ChienS, HenrionD and PatapoutianA. GPR68 is a sensor of shear stress in endothelial cells of small-diameter arteries and regulates flow-mediated dilation and remodeling. Cell 2018;173(3):762-775.
    • Roy C, Tabiasco J, Caillon A, Delneste Y, Merot J, Favre J, Guihot AL, Martin L, Nascimento DC, Ryffel B, Robson SC, Sévigny J, Henrion D, Kauffenstein G. Loss of vascular expression of nucleoside triphosphate diphosphohydrolase-1/CD39 in hypertension. Purinergic Signal. 2018;14(1):73-82.
    • Geffroy G, Benyahia R, Frey S, Desquiret-Dumas V, Gueguen N, Bris C, Belal S, Inisan A, Renaud A, Chevrollier A, Henrion D, Bonneau D, Letournel F, Lenaers G, Reynier P, Procaccio V. The accumulation of assembly intermediates of the mitochondrial complex I matrix arm is reduced by limiting glucose uptake in a neuronal-like model of MELAS syndrome. Biochim Biophys Acta. 2018; 1864(5 Pt A):1596-1608.
    • Kauffenstein G, Yegutkin GG, Khiati S, Pomozi V, Le Saux O, Leftheriotis G, Lenaers G, Henrion D, Martin L. Alteration of Extracellular Nucleotide Metabolism in Pseudoxanthoma Elasticum. J Invest Dermatol. 2018 Feb 28. pii: S0022-202X(18)30148-9
    • Valenzuela R, Costa-Besada MA, Iglesias-Gonzalez J, Perez-Costas E, Villar-Cheda B, Garrido-Gil P, Melendez-Ferro M, Soto-Otero R, Lanciego JL, Henrion D, Franco R, Labandeira-Garcia JL. Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration. Cell Death Dis. 2016;7(10):e2427.
    • Caillon A, Grenier C, Grimaud L, Vessieres E, Guihot AL, Blanchard S, Lelievre E, Chabbert M, Foucher ED, Jeannin P, Beauvillain C, Abraham P, Loufrani L, Delneste Y, Henrion D. The angiotensin II type 2 receptor activates flow-mediated outward remodelling through T cells-dependent interleukin-17 production. Cardiovasc Res. 2016;112(1):515-25
    • Kauffenstein G, Tamareille S, Prunier F, Roy C, Ayer A, Toutain B, Billaud M, Isakson BE, Grimaud L, Loufrani L, Rousseau P, Abraham P, Procaccio V, Monyer H, de Wit C, Boeynaems JM, Robaye B, Kwak BR, Henrion D. Central Role of P2Y6 UDP Receptor in Arteriolar Myogenic Tone. Arterioscler Thromb Vasc Biol. 2016;36:1598-606.
    • Retailleau K, Arhatte M, Demolombe S, Peyronnet R, Baudrie V, Jodar M, Bourreau J, Henrion D, Offermanns S, Nakamura F, Feng Y, Patel A, Duprat F, Honoré E. Arterial Myogenic Activation through Smooth Muscle Filamin A. Cell Rep. 2016;14:2050-8.
    • Kauffenstein G, Pizard A, Le Corre Y, Vessières E, Grimaud L, Toutain B, Labat C, Mauras Y, Gorgels TG, Bergen AA, Le Saux O, Lacolley P, Lefthériotis G, Henrion D, Martin L. Disseminated Arterial Calcification and Enhanced Myogenic Response Are Associated With Abcc6 Deficiency in a Mouse Model of Pseudoxanthoma Elasticum. Arterioscler Thromb Vasc Biol. 2014 34:1045-56.
    • Belizna C, Loufrani L, Ghali A, Lahary A, Primard E, Louvel JP, Henrion D, Lévesque H, Ifrah N. Arterial Stiffness and Stroke in Sickle Cell Disease. Stroke. 2012, 43:1129-30.
    • Belizna C, Loufrani L, Subra JF, Godin M, Jolly P, Vitecocq O, Faller B, Ghali A, Tron F, Hamidou M, Henrion D, Lévesque H, Ifrah N. A 5-year prospective follow-up study in essential cryofibrinogenemia patients. Autoimmun Rev. 2011;10:559-62.
    • Bergaya S, Faure S, Rio M, Escoubet B, Baudrie V, Bonnin P, Henrion D, Loirand G, Achard JM, Jeunemaitre X,  Hadchouel J. L. WNK1 regulates vascular contraction and myogenic response. Hypertension. 2011, 58:439-45.
    • Pinaud F, Loufrani L, Toutain B, Lambert D, Vandekerckhove L, Henrion D, Baufreton C. In vitro protection of vascular function from oxidative stress and inflammation by pulsatility in resistance arteries. J Thorac Cardiovasc Surg. 2011;142:1254-62.
    • 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.
    • Guilluy C, Brégeon J, Toumaniantz G, Rolli-Derkinderen M, Retailleau K, Loufrani L, HenrionD,  Scalbert E, Bril A, Torres R, Offermanns S, Pacaud P, Loirand G. The Rho exchange factor Arhgef1: How Angiotensin II- regulates vascular tone and mediates hypertension. Nature Medicine, 2010;16:183-90.
    • 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.
    • 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;1:145.
    • Kauffenstein G, Drouin A, Thorin-Trescases N, Bachelard H, Robaye B, D'Orléans-Juste P, Marceau F, Thorin E, Sévigny J. NTPDase1 (CD39) controls nucleotide-dependent vasoconstriction in mouse. Cardiovasc Res 2010 ;85: 204-13.
    • Kauffenstein G, Fürstenau CR, D'Orléans-Juste P, Sévigny J. The ecto-nucleotidase NTPDase1 differentially regulates P2Y1 and P2Y2 receptor-dependent vasorelaxation. Br J Pharmacol. 2010;159:576-85.
    • Guilluy C, Rolli-Derkinderen M, Loufrani L, Bourgé A, Henrion D, Sabourin L, Loirand G, Pacaud P.  Ste20-related kinase SLK phosphorylates Ser 188 of RhoA to induce vasodilation in response to Angiotensin II type 2 receptor activation. Circ. Res. 2008;102:1265-74.
    • Dubroca C, Loyer X, Retailleau K, Loirand G, Pacaud P, Feron O, Balligand JL, Lévy BI, Heymes C, Henrion D. RhoA activation and interaction with Caveolin-1 are critical for pressure-induced myogenic tone in rat mesenteric resistance arteries. Cardiovasc Res. 2007;73:190-7.
    • Pinaud F, Bocquet A, Dumont O, Retailleau K, Baufreton C, Andriantsitohaina R, Loufrani L, Henrion D. Paradoxical Role of Angiotensin II Type 2 Receptors in Resistance Arteries of Old Rats. Hypertension 2007;50:96-102.
    • Rolli-Derkinderen M, Sauzeau V, Boyer L, Lemichez E, Baron C, Henrion D, Loirand G , Pacaud P.  Phosphorylation of Serine 188 protects RhoA from UbPhosphorylation of Serine 188 protects RhoA from Ubiquitin/proteasome-mediated Degradation. Circ. Res. 2005; 96:1152-60.
    • 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.