Matrix Metalloproteinase 2 and 9 Dysfunction Underlie Vascular Stiffness in Circadian Clock Mutant Mice

  • Anea C
  • Ali M
  • Osmond J
 et al. 
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Abstract

OBJECTIVE To determine if elasticity in blood vessels is compromised in circadian clock-mutant mice (Bmal1-knockout [KO] and Per-triple KO) and if matrix metalloproteinases (MMPs) might confer these changes in compliance. METHODS AND RESULTS High-resolution ultrasonography in vivo revealed impaired remodeling and increased pulse-wave velocity in the arteries of Bmal1-KO and Per-triple KO mice. In addition, compliance of remodeled arteries and naïve pressurized arterioles ex vivo from Bmal1-KO and Per-triple KO mice was reduced, consistent with stiffening of the vascular bed. The observed vascular stiffness was coincident with dysregulation of MMP-2 and MMP-9 in Bmal1-KO mice. Furthermore, inhibition of MMPs improved indexes of pathological remodeling in wild-type mice, but the effect was abolished in Bmal1-KO mice. CONCLUSIONS Circadian clock dysfunction contributes to hardening of arteries, which may involve impaired control of the extracellular matrix composition.

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Authors

  • C. B. Anea

  • M. I. Ali

  • J. M. Osmond

  • J. C. Sullivan

  • D. W. Stepp

  • A. M. Merloiu

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