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Sex-Dependent Impairment of Endothelium-Dependent Relaxation in Aorta of Mice with Overexpression of Hyaluronan in Tunica Media

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  • Karen Axelgaard Lorentzen, Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus UniversityAarhus, Denmark.
  • ,
  • Raquel Hernanz, Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus UniversityAarhus, Denmark., Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos
  • ,
  • Estéfano Pinilla
  • Jens Randel Nyengaard
  • Lise Wogensen
  • Ulf Simonsen

Diabetic macroangiopathy is characterized by increased extracellular matrix deposition, including excessive hyaluronan accumulation, vessel thickening and stiffness, and endothelial dysfunction in large arteries. We hypothesized that the overexpression of hyaluronan in the tunica media also led to endothelial cell (EC) dysfunction. To address this hypothesis, we investigated the following in the aortas of mice with excessive hyaluronan accumulation in the tunica media (HAS-2) and wild-type mice: EC dysfunction via myograph studies, nitric oxide (NO) bioavailability via diaminofluorescence, superoxide formation via dihydroethidium fluorescence, and the distances between ECs via stereological methods. EC dysfunction, characterized by blunted relaxations in response to acetylcholine and decreased NO bioavailability, was found in the aortas of male HAS-2 mice, while it was unaltered in the aortas of female HAS-2 mice. Superoxide levels increased and extracellular superoxide dismutase (ecSOD) expression decreased in the aortas of male and female HAS-2 mice. The EC-EC distances and LDL receptor expression were markedly increased in the HAS-2 aortas of male mice. Our findings suggest hyaluronan increases oxidative stress in the vascular wall and that together with increased EC distance, it is associated with a sex-specific decrease in NO levels and endothelial dysfunction in the aorta of male HAS-2 transgenic mice.

Original languageEnglish
Article number8436
JournalInternational Journal of Molecular Sciences
Publication statusPublished - 8 May 2023

    Research areas

  • Animals, Aorta/metabolism, Endothelium, Vascular/metabolism, Female, Hyaluronic Acid/metabolism, Male, Mice, Mice, Transgenic, Nitric Oxide Synthase Type III/metabolism, Nitric Oxide/metabolism, Superoxides/metabolism, Tunica Media/metabolism, Vascular Diseases/metabolism, Vasodilation

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