title: Angiotensin II-dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis.
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.
authors.forename: Elena M
authors.initials: EM
authors.lastname: Gallo
authors.forename: David C
authors.initials: DC
authors.lastname: Loch
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Habashi
authors.forename: Juan F
authors.initials: JF
authors.lastname: Calderon
authors.forename: Yichun
authors.initials: Y
authors.lastname: Chen
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Christel
authors.initials: C
authors.lastname: van Erp
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Gerber
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Parker
authors.forename: Kimberly
authors.initials: K
authors.lastname: Sauls
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.forename: Sara K
authors.initials: SK
authors.lastname: Cooke
authors.forename: Mark E
authors.initials: ME
authors.lastname: Lindsay
authors.forename: Rosanne
authors.initials: R
authors.lastname: Rouf
authors.forename: Loretha
authors.initials: L
authors.lastname: Myers
authors.forename: Colette M
authors.initials: CM
authors.lastname: ap Rhys
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Kent
authors.forename: Russell A
authors.initials: RA
authors.lastname: Norris
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000473:pathology; D001014:Aortic Aneurysm / Q000378:metabolism* / Q000517:prevention & control; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D055947:Loeys-Dietz Syndrome / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019808:Losartan / Q000627:therapeutic use; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse; D019808:Losartan