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Smooth muscle filamin A is a major determinant of conduit artery structure and function at the adult stage

  • Integrative physiology
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Abstract

Human mutations in the X-linked FLNA gene are associated with a remarkably diverse phenotype, including severe arterial morphological anomalies. However, the role for filamin A (FlnA) in vascular cells remains partially understood. We used a smooth muscle (sm)-specific conditional mouse model to delete FlnA at the adult stage, thus avoiding the developmental effects of the knock-out. Inactivation of smFlnA in adult mice significantly lowered blood pressure, together with a decrease in pulse pressure. However, both the aorta and carotid arteries showed a major outward hypertrophic remodeling, resistant to losartan, and normally occurring in hypertensive conditions. Notably, arterial compliance was significantly enhanced in the absence of smFlnA. Moreover, reactivity of thoracic aorta rings to a variety of vasoconstrictors was elevated, while basal contractility in response to KCl depolarization was reduced. Enhanced reactivity to the thromboxane A2 receptor agonist U46619 was fully reversed by the ROCK inhibitor Y27632. We discuss the possibility that a reduction in arterial stiffness upon smFlnA inactivation might cause a compensatory increase in conduit artery diameter for normalization of parietal tension, independently of the ROCK pathway. In conclusion, deletion of smFlnA in adult mice recapitulates the vascular phenotype of human bilateral periventricular nodular heterotopia, culminating in aortic dilatation.

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Acknowledgments

We are grateful to the Agence Nationale de la Recherche (ANR) for ANR 2008 “Du gène à la physiopathologie; des maladies rares aux maladies communes” and ANR 2011 “Physiologie, physiopathologie, santé publique”, to the Fondation de la recherche médicale, to the Fondation de recherche sur l’hypertension artérielle, to the Fondation de France, to the Fondation Lefoulon-Delalande, to the Société Française d’hypertension artérielle, to the Université de Nice Sophia Antipolis, to the Centre National de la Recherche Scientifique (CNRS) “défi mécanobiologie” and to the Institut National de la Santé et de la Recherche Médicale (Inserm) for financial support. We thank Dr. Fumihiko Nakamura for providing the 1–7 monoclonal FlnA antibody.

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    Authors and Affiliations

    1. Institut de Pharmacologie Moléculaire et Cellulaire, LabEx ICST, UMR 7275 CNRS, Université de Nice Sophia Antipolis, Valbonne, France

      Kevin Retailleau, Malika Arhatte, Sophie Demolombe, Martine Jodar, Amanda Patel, Eric Honoré & Fabrice Duprat

    2. INSERM U970, PARCC-Université Paris Descartes-Hôpital Européen Georges Pompidou, AP-HP, Paris, 75015, France

      Véronique Baudrie

    3. Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany

      Stefan Offermanns

    4. Department of Neurology, Northwestern University, Chicago, IL, USA

      Yuanyi Feng

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    1. Kevin Retailleau
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    Correspondence to Eric Honoré.

    Additional information

    Eric Honoré and Fabrice Duprat are both co-last authors

    Kevin Retailleau and Malika Arhatte contributed equally to this work.

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    Fig. S1

    Low blood pressure in the absence of smFlnA. a) Diastolic arterial pressure, recorded using telemetry at day and night times as indicated, in conscious smFlnA0/+ (white bars) or smFlnA0/- (black bars) mice at 12 weeks post-TAM induction, b) Systolic arterial pressure, and c) Pulse pressure in the same animals as in a. Number of mice analyzed is indicated at the bottom of the graphs. (PDF 27 kb)

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    Retailleau, K., Arhatte, M., Demolombe, S. et al. Smooth muscle filamin A is a major determinant of conduit artery structure and function at the adult stage. Pflugers Arch - Eur J Physiol 468, 1151–1160 (2016). https://doi.org/10.1007/s00424-016-1813-x

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