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    Role of cytoskeletal proteins in microvascular mechanotransduction

    Role of cytoskeletal proteins in microvascular mechanotransduction

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    Laurent Loufrani

    Photo Laurent Loufrani

    Team members : 

    • Laurent Loufrani, Ph.D.
    • Frédérique Pinaud, M.D., Ph.D.
    • Olivier Fouquet, M.D., Ph.D.
    • Linda Grimaud, assistant-engineer
    • Céline Grenier, PhD Student
    • Tristan Champin, PhD Student
    • Simon Dagvan, Undergraduate student

    Resistance arteries represent the majority of the vascular tree. In these vessels, pressure induces a contraction (myogenic tone) and flow (shear stress) a dilation. In physiological conditions pressure and flow-dependent tone interact to allow blood flow regulation in downstream located tissues. In pathological situations (hypertension, diabetes or myopathies…), blood flow is not efficiently controlled with dramatic consequences. In cytoskeletal deficiency, we found strong changes in flow-dependent dilation in arteries from mice lacking vimentin, desmin or dystrophin. These vascular defects are associated to a deficiency in microvascular remodeling after chronic changes in blood flow. Thus it is now important to determine the consequences of these vascular disorders related to changes in cytoskeletal proteins arrangement, as well as the exact role of these proteins in the mechanotransduction (pressure and flow) pathways in the microcirculation. Flow-related transduction pathways in resistance arteries will be studied in acute (flow-mediated dilation) and chronic conditions (remodeling), in physiological and pathological situations. Furthermore, our team is also studying the involvement of circulating cells (macrophages, neutrophil cells, platelets…) in the microcirculation (inflammation, remodeling…)

    Our team use molecular biology, biochemistry, or confocal and intravital microscopy. Physiological aspects are also studied with arteriographs allowing the control of pressure and flow in isolated resistance arteries in vitro. Changes in diameter in response to flow (vasodilation) or pressure (contraction) will be correlated to the activation of proteins potentially involved in the response: integrins, adhesion molecules such as PECAM or P-selectin, dystrophin, δ-sarcoglycan, caveolin or filamin. Those signaling pathways will be studied in culture cells, control animals and in mice lacking a protein.


    Chronic changes in blood flow will be induced locally in mesenteric resistance by microsurgery. In  parallel, human arteries will be used in areriographs and organ-culture myograph in order to validate in humans the pathways discovered in mice arteries.

    This study will open new therapeutic ways in the pathological situations involving mutations in the proteins involved in the pathways investigated, as well as in other diseases involving the microcirculation which remains minimally studied, by contrast to the large amount of diseases involving mainly the microcirculation.

     

    Collaborations :

    CHU Angers, France

    Institut du thorax, INSERM915, Nantes, France

    Le Paris-Centre de recherche Cardiovasculaire (PARCC), Paris , France

    Centre de Recherche des Cordeliers, Paris, France

    AFM, Paris, France

    Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Allemagne

     

    Research articles :

    •  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.
    •  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, Paulin D, Lévy BI, Henrion D. Excessive Microvascular Adaptation to Changes in Blood Flow in Mice Lacking the Gene Encoding for Desmin. Arterioscl Thromb Vasc Biol 2002; 22:1579-84.
    • Loufrani L, Lévy BI, Henrion D. Defect in microvascular adaptation to chronic changes in blood flow in mice lacking Dystrophin. Cir. Res 2002; 91(12):1183-89.
    • D. You, L. Loufrani, K. Matrougui, B. Levy, R.E Widdop, D. Henrion. High blood pressure reverses AT2 receptor-mediated vasodilation in spontaneously hypertensive rats. Circulation 2005;111(8):1006-11.
    • Loufrani L, Dubroca C, Li Z, Lévy BI, Paulin D, Henrion D. The absence of dystrophin in mice reduces NO-dependent vascular function: total recovery after a treatment with the aminoglycoside gentamicin. Arterioscl Thromb Vasc Biol 2004 Apr;24(4):671-6.
    • Laurent Loufrani, Daniel Henrion. Vasodilator treatment with hydralazine increases blood flow in mdx mice resistance arteries without vascular wall remodeling or endothelium function improvement. J.Hypertension 2005 oct 23(10):1855-60.
    • Baron-Menguy C, Bocquet A, Guihot AL, Chappard D, Amiot MJ, Andriantsitohaina R, Loufrani L, Henrion D. Effects of red wine polyphenols on postischemic neovascularization model in rats: low doses are proangiogenic, high doses anti-angiogenic. FASEB J. 2007 Nov;21(13):3511-21.
    • Loufrani L, Retailleau K, Bocquet A, Dumont O, Danker K, Louis H, Lacolley P, Henrion D. Key role of alpha(1)beta(1)-integrin in the activation of PI3-kinase-Akt by flow (shear stress) in resistance arteries. Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1906-13.
    • Loufrani L, Henrion D. Role of the cytoskeleton in flow (shear stress)-induced dilation and remodeling in resistance arteries. Med Biol Eng Comput. 2008 Feb 2.
    • Guilluy C, Rolli-Derkinderen M, Loufrani L, Bourgé A, Henrion D, Sabourin L, Loirand G, Pacaud P. Ste20-related kinase SLK phosphorylates Ser188 of RhoA to induce vasodilation in response to angiotensin II Type 2 receptor activation. Circ Res. 2008 May 23;102(10):1265-74.
    • Sharif-Naeini R, Folgering JH, Bichet D, Duprat F, Lauritzen I, Arhatte M, Jodar M, Dedman A, Chatelain FC, Schulte U, Retailleau K, Loufrani L, Patel A, Sachs F, Delmas P, Peters DJ, Honoré E.Polycystin-1 and -2 dosage regulates pressure sensing. Cell. 2009 Oct 30;139(3):587-96.
    • 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 Jan;55(1):109-15
    • Retailleau K, Belin de Chantemèle EJ, Chanoine S, Guihot AL, Vessières E, Toutain B, Faure S, Bagi Z, Loufrani L, Henrion D. Reactive oxygen species and cyclooxygenase 2-derived thromboxane A2 reduce angiotensin II type 2 receptor vasorelaxation in diabetic rat resistance arteries. Hypertension. 2010 Feb;55(2):339-44.
    • Belin de Chantemèle EJ, Vessières 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 Jun 1;86(3):516-25.
    • Guilluy C, Brégeon J, Toumaniantz G, Rolli-Derkinderen M, Retailleau K, Loufrani L, Henrion D, Scalbert E, Bril A, Torres RM, Offermanns S, Pacaud P, Loirand G. The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure. Nat Med. 2010 Feb;16(2):183-90.
    • Nguyen Dinh Cat A, Griol-Charhbili V, Loufrani L, Labat C, Benjamin L, Farman N, Lacolley P, Henrion D, Jaisser F. The endothelial mineralocorticoid receptor regulates asoconstrictor tone and blood pressure. FASEB J. 2010 Jul;24(7):2454-63.
    • Buschmann I, Pries A, Styp-Rekowska B, Hillmeister P, Loufrani L, Henrion D, Shi Y, Duelsner A, Hoefer I, Gatzke N, Wang H, Lehmann K, Ulm L, Ritter Z, Hauff P, Hlushchuk R, Djonov V, van Veen T, le Noble F. Pulsatile shear and Gja5 modulate arterial identity and remodeling events during flow-driven arteriogenesis. Development. 2010 Jul;137(13):2187-96.
    • Baron-Menguy C, Toutain B, Cousin M, Dumont O, Guihot 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 Aug;33(8):857-66.
    • 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 Nov;142(5):1254-62.
    • 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 Jul;10(9):559-62.
    • 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 Jul;10(9):559-62.
    • 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
    • Retailleau K, Toutain B, Galmiche G, Fassot C, Sharif-Naeini R, Kauffenstein G, Mericskay M, Duprat F, Grimaud L, Merot J, Lardeux A, Pizard A, Baudrie V, Jeunemaitre X, Feil R, Göthert JR, Lacolley P, Henrion D, Li Z, Loufrani L. Selective involvement of serum response factor in pressure-induced myogenic tone in resistance arteries. Arterioscler Thromb Vasc Biol. 2013 Feb;33(2):339-46
    • Galmiche G, Labat C, Mericskay M, Ait Aissa K, Blanc J, Retailleau K, Bourhim M, Coletti D, Loufrani L, Gao-Li J, Feil R, Challande P, Henrion D, Decaux JF, Regnault V, Lacolley P, Li Z. Inactivation of Serum Response Factor Contributes To Decrease Vascular Muscular Tone and Arterial Stiffness in Mice. Circ Res. 2013 Feb 20.