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MitoVasc : physiopathologie cardiovasculaire et mitochondriale


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    Neurosecretion, Stress and vascular fonction

    Neurosecretion, Stress and vascular fonction

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    Christian Legros







    Team members : 

    Christian Legros, Ph.D.

    César Mattei, Ph.D.

    Frédéric De Nardi, Ph.D.

    Lucille Crespin (Ph.D. Student)

    Joseph Khoury (Ph.D. Student)

    Zineb Soualah (Ph.D. Student)

      

    Our team is interested in elucidating the links between stress and vascular pathologies. Our organism is daily subjected to changes in its environment, often perceived as stressors. To cope with a changing environment, our organism triggers physiological and adaptive responses. Activation of the stress system leads to behavioural and hormonal changes that improve the ability of the organism to adjust a state of “threatened” homeostasis and increase its chances for survival. The body’s principal adaptive responses to stress stimuli are mediated by an intricate stress system, which includes a synergistic activation of both neuronal and neuroendocrine axis. The neuronal axis, also called sympathoadrenal system consists of sympathetic post-ganglionic neurons and adrenal medullary chromaffin cells. Acute activation of the sympathoadrenal system gives rise to increased production by the adrenal chromaffin cells of catecholamines, mainly epinephrine and norepinephrine. Once delivered into the blood circulation in response to stress, catecholamines exert multiple actions in particular on the cardiovascular system, leading to appropriate adjustments of blood pressure and cardiac rhythm, and on the energy metabolism, enabling the organism to cope with a threat for its survival. Nevertheless, cumulative burden of repetitive or prolonged environmental, physiological or psychological stress challenges can dysregulate the stress system and contribute to the development of a variety of illnesses including vascular pathologies such as hypertension, atherosclerosis, and the insulin-resistance-dyslipidemia syndrome.

    Our research investigates the role and the contribution of the adrenal medullary tissue in the etiology of stress-associated vascular pathologies. More precisely, we are currently studying the remodelling and the plasticity of the adrenal stimulus-secretion coupling leading to catecholamine secretion, in different animal models of stress (rat exposed to cold,…) or vascular diseases (SHR rats as a model of genetic hypertension,…). To achieve this, we use an original methodological approach on acute adrenal slices. Our technical approaches allow real-time observation of cellular and multicellular signalling in the chromaffin cell network. Electrophysiology (patch-clamp) is used to monitor electrical activity of single chromaffin cell or chromaffin cell pairs. Catecholamine release is monitored by amperometry in acute slices. Real-time Ca2+ confocal microscopy is used to image changes in intracellular Ca2+ concentration, the main second messenger involved in triggering hormonal secretion. In combination with these techniques of integrative neurobiology, we also use molecular biology to investigate the stimulus-secretion coupling at the transcriptional level (qPCR on messenger RNAs and microRNAs), biochemistry and immohistofluorescence.

    In addition, the team is also engaged in characterizing the vascular effects of neurosecretory factors which are co-released with catecholamines from adrenal chromaffin cells. Our studies are focused on chromogranins and chromogranin-derived peptides (catestatin,…). This is achieved by the use of integrative physiology techniques involving myography and arteriography, that allow to determine the vascular reactivity of blood vessels.

     


    Figure 1 : Action potential-induced multicellular [Ca2+]i rises in response to a burst of action potentiels evoked in a single chromaffin cell (acute adrenal slice). From Martin et coll., J. Neurosci., 2001

     


    Figure 2 : Spontaneous excitatory synaptic activity, recorded in a chromaffin cell. Left : control activity. Right : activity recorded in the same cell, in the presence of a toxin which  selectively blocks alpha9/alpha10 nicotinic receptors. From Colomer et coll., J. Neurosci., 2010.

     

    Collaborations

    - Dr. Sheriar G. HORMUZDI, Centre for Neurosciences, Division of Medical Sciences, University of Dundee, Dundee (UNITED KINGDOM)

    - Dr. Michel G. DESARMENIEN, Institute of Functional Genomics, CNRS UMR5203, INSERM U661, University of Montpellier 1 and 2, Montpellier (FRANCE)

    - Dr. Arnaud MONTEIL, Institute of Functional Genomics, CNRS UMR5203, INSERM U661, University of Montpellier 1 and 2, Montpellier (FRANCE)

    - Dr. Antonio R. ARTALEJO, Department of Pharmacology and Toxicology, Complutense University of Madrid, Madrid (SPAIN)

    - Dr. Emilio CARBONE, Department of Neuroscience, National Institute of Neuroscience, University of Torino, Torino (ITALY)

    - Dr. Ke DONG, Department of Entomology, Genetic and Neuroscience Programs, University of Michigan, Michigan (USA)

    - Dr. Marc VERLEYE, Société Biocodex, Service de Pharmacologie, Compiègne (FRANCE)

     

    Most significant publications (from 2008)


    Peer-reviewed articles

    - Colomer C, Olivos Ore LA, Coutry N, Mathieu MN, Arthaud S, Fontanaud P, Iankova I, Macari F, Thouënnon E, Yon L, Anouar Y, Guérineau NC (2008). Functional remodeling of gap junction-mediated electrical communication between adrenal chromaffin cells in stressed rats. J Neurosci 28:6616-6626.

    - Colomer C, Lafont C, Guérineau NC (2008). Stress-induced intercellular communication remodeling in the rat adrenal medulla. Ann N Y Acad Sci 1148:106-111.

    - Colomer C, Olivos-Oré LA, Vincent A, McIntosh JM, Artalejo AR, Guérineau NC (2010). Functional characterization of alpha9-containing cholinergic nicotinic receptors in the rat adrenal medulla: implication in stress-induced functional plasticity.J Neurosci 30:6732-6742.

    - Desarménien MG, Jourdan C, Toutain B, Vessières E, Hormuzdi SG, Guérineau NC (2013) Gap junction signaling is a stress-regulated component of adrenal neuroendocrinestimulus-secretion coupling in vivo. Nat Commun, 4:2938. doi:10.1038/ncomms3938.

     

    Reviews

    - Colomer C, Desarménien MG, Guérineau NC (2009). Revisiting the stimulus-secretion coupling in the adrenal medulla: role of gap junction-mediated intercellular communication. Mol Neurobiol 40:87-100.

    - Guérineau NC, Desarménien MG (2010). Developmental and stress-induced remodeling of cell-cell communication in the adrenal medullary tissue. Cell Mol Neurobiol 30:1425-1431.

    - Colomer C, Martin AO, Desarménien MG, Guérineau NC (2012). Gap junction-mediated intercellular communication in the adrenal medulla: an additional ingredient of stimulus-secretion coupling regulation. Biochim Biophys Acta, 1818:1937-1951.

    - Guérineau NC, Desarménien MG, Carabelli V, Carbone E (2012) Functional chromaffin cell plasticity in response to stress: focus on nicotinic, gap junction and voltage-gated Ca2+ channels. J Mol Neurosci, 48:368-386.

    - Kauffenstein G, Laher I, Matrougui K, Guérineau NC, Henrion D (2012) Emerging role of G protein-coupled receptors in microvascular myogenic tone. Cardiovasc Res, 95:223-232.

     

    Others

    - Carbone E, Guérineau NC, Loh YP, Zhou Z (2012) Commentary: Ion channels, fusion pores and exocytosis. J Mol Neurosci, 48:357-359.