Journal Article

Angiotensin II–dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis

Gallo, Elena M., Calderon, Juan F., Rouf, Rosanne, Chen, Yichun, van Erp, Christel, Lindsay, Mark E., Sauls, Kimberly, Habashi, Jennifer P., Gerber, Elizabeth E., Parker, Sarah J., Cooke, Sara K., Judge, Daniel P., Bedja, Djahida, Huso, David L., ap Rhys, Colette M., Kent, Kathleen C., Dietz, Harry C., Myers, Loretha, Loch, David C., Norris, Russell A.

2014

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Angiotensin / Angiotensin II - physiology / Angiotensin II Type 1 Receptor Blockers - therapeutic use / Animals / Aorta - pathology / Aortic Aneurysm - metabolism / Aortic Aneurysm - prevention & control / Cells, Cultured / Cellular signal transduction / Connective tissue diseases / Development and progression / Disease Progression / Female / Genetic aspects / 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 / Physiological aspects / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - metabolism / Receptors, Transforming Growth Factor beta - genetics / Receptors, Transforming Growth Factor beta - metabolism / Signal Transduction / Smad2 Protein - metabolism / Transforming Growth Factor beta - metabolism / Transforming growth factors