Angiotensin II-dependent TGF-β Signaling Contributes to Loeys-Dietz Syndrome Vascular Pathogenesis

J Clin Invest. 2014 Jan;124(1):448-60. doi: 10.1172/JCI69666. Epub 2013 Dec 20.

Abstract

Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is characterized by a high risk for aneurysm and dissection throughout the arterial tree and phenotypically resembles Marfan syndrome. LDS is caused by heterozygous missense mutations in either TGF-β receptor gene (TGFBR1 or TGFBR2), which are predicted to result in diminished TGF-β signaling; however, aortic surgical samples from patients show evidence of paradoxically increased TGF-β signaling. We generated 2 knockin mouse strains with LDS mutations in either Tgfbr1 or Tgfbr2 and a transgenic mouse overexpressing mutant Tgfbr2. Knockin and transgenic mice, but not haploinsufficient animals, recapitulated the LDS phenotype. While heterozygous mutant cells had diminished signaling in response to exogenous TGF-β in vitro, they maintained normal levels of Smad2 phosphorylation under steady-state culture conditions, suggesting a chronic compensation. Analysis of TGF-β signaling in the aortic wall in vivo revealed progressive upregulation of Smad2 phosphorylation and TGF-β target gene output, which paralleled worsening of aneurysm pathology and coincided with upregulation of TGF-β1 ligand expression. Importantly, suppression of Smad2 phosphorylation and TGF-β1 expression correlated with the therapeutic efficacy of the angiotensin II type 1 receptor antagonist losartan. Together, these data suggest that increased TGF-β signaling contributes to postnatal aneurysm progression in LDS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / physiology*
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Animals
  • Aorta / pathology
  • Aortic Aneurysm / metabolism*
  • Aortic Aneurysm / prevention & control
  • Cells, Cultured
  • Disease Progression
  • Female
  • Haploinsufficiency
  • Humans
  • Loeys-Dietz Syndrome / drug therapy
  • Loeys-Dietz Syndrome / metabolism*
  • Loeys-Dietz Syndrome / pathology
  • Losartan / therapeutic use
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation, Missense
  • Myocytes, Smooth Muscle / metabolism
  • Phenotype
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction
  • Smad2 Protein / metabolism
  • Transforming Growth Factor beta / metabolism*

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Receptors, Transforming Growth Factor beta
  • Smad2 Protein
  • Transforming Growth Factor beta
  • Angiotensin II
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse
  • Losartan