Activation of AcvR1-Mediated Signaling Results in Semilunar Valve Defects

Shabber Syed, Sudha Rajderkar, Jeffrey M. Mann, Travis Hawkins, Bingrou Wu, Bin Zhou, Yukiko Sugi, Yuji Mishina, Vesa Kaartinen

Research output: Contribution to journalArticlepeer-review

Abstract

Calcific aortic valve disease (CAVD) is a common cardiac defect, particularly in the aging population. While several risk factors, such as bi-leaflet valve structure and old age, have been identified in CAVD pathogenesis, molecular mechanisms resulting in this condition are still under active investigation. Bone morphogenetic protein signaling via the activin type I receptor (AcvRI) plays an important role during physiological and pathological processes involving calcification, e.g., bone formation and heterotopic ossification. In addition, AcvRI is required for normal cardiac valve development, yet its role in aortic valve disease, if any, is currently unknown. Here, we induced the expression of constitutively active AcvRI in developing mouse embryos in the endocardium and in cells at the valve leaflet–wall junction that are not of endocardium origin using the Nfac1Cre transgene. The mutant mice were born alive, but showed thickened aortic and pulmonary valve leaflets during the early postnatal period. Adult mutant mice developed aortic stenosis with high frequency, sclerotic aortic valves, and displayed Alcian Blue-positive hypertrophic chondrocyte-like cells at the leaflet–wall junction. Calcification was only seen with low penetrance. In addition, we observed that the expression levels of gene sets associated with inflammation-related cytokine signaling, smooth muscle cell contraction, and cGMP signaling were altered in the mutants when compared with those of the controls. This work shows that, in a mouse model, such continuous AcvRI activity in the Nfatc1Cre recombination domain results in pathological changes in the aortic valve structure and function.

Original languageEnglish (US)
Article number272
JournalJournal of Cardiovascular Development and Disease
Volume9
Issue number8
DOIs
StatePublished - Aug 2022

Keywords

  • TGF-beta superfamily signaling
  • calcification
  • valve defects

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of 'Activation of AcvR1-Mediated Signaling Results in Semilunar Valve Defects'. Together they form a unique fingerprint.

Cite this