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

Kevin Retailleau, Malika Arhatte, Sophie Demolombe, Martine Jodar, Véronique Baudrie, Stefan Offermanns, Yuanyi Feng, Amanda Patel, Eric Honoré*, Fabrice Duprat

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1151-1160
Number of pages10
JournalPflugers Archiv European Journal of Physiology
Volume468
Issue number7
DOIs
StatePublished - Jul 1 2016

Keywords

  • Aorta
  • Blood pressure
  • Carotid
  • Contractility
  • Filamin A
  • Reactivity
  • Remodeling
  • Stiffness

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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