title: Smooth muscle filamin A is a major determinant of conduit artery structure and function at the adult stage.
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.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, LabEx ICST, UMR 7275 CNRS, Université de Nice Sophia Antipolis, Valbonne, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Retailleau
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, LabEx ICST, UMR 7275 CNRS, Université de Nice Sophia Antipolis, Valbonne, France.
authors.forename: Malika
authors.initials: M
authors.lastname: Arhatte
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, LabEx ICST, UMR 7275 CNRS, Université de Nice Sophia Antipolis, Valbonne, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Demolombe
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, LabEx ICST, UMR 7275 CNRS, Université de Nice Sophia Antipolis, Valbonne, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Jodar
authors.affiliation: INSERM U970, PARCC-Université Paris Descartes-Hôpital Européen Georges Pompidou, AP-HP, Paris, 75015, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Baudrie
authors.affiliation: Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Department of Neurology, Northwestern University, Chicago, IL, USA.
authors.forename: Yuanyi
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, LabEx ICST, UMR 7275 CNRS, Université de Nice Sophia Antipolis, Valbonne, France.
authors.forename: Amanda
authors.initials: A
authors.lastname: Patel
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, LabEx ICST, UMR 7275 CNRS, Université de Nice Sophia Antipolis, Valbonne, France. honore@ipmc.cnrs.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Honoré
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, LabEx ICST, UMR 7275 CNRS, Université de Nice Sophia Antipolis, Valbonne, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Duprat
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D064448:Filamins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010641:Phenotype; D059289:Vascular Stiffness / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D064448:Filamins; D014662:Vasoconstrictor Agents
keywords: Aorta; Blood pressure; Carotid; Contractility; Filamin A; Reactivity; Remodeling; Stiffness