Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome

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dc.contributor.authorGallo MacFarlane, Elena
dc.contributor.authorParker, Sarah J.
dc.contributor.authorShin, Josep Y.
dc.contributor.authorKang, Benjamin E.
dc.contributor.authorZiegler, Shira G.
dc.contributor.authorCreamer, Tyler J.
dc.contributor.authorBagirzadeh, Rustam
dc.contributor.authorBedja, Djahida
dc.contributor.authorChen, Yichun
dc.contributor.authorCalderón, Juan Francisco
dc.contributor.authorWeissier, Katherine
dc.contributor.authorFrischmeyer-Guerrerio, Pamela A.
dc.contributor.authorLindsay, Mark E.
dc.contributor.authorHabashi, Jennifer P.
dc.contributor.authorDietz, Harry C.
dc.date.accessioned2022-06-17T21:40:30Z
dc.date.available2022-06-17T21:40:30Z
dc.date.issued2019
dc.description.abstractThe aortic root is the predominant site for development of aneurysm caused by heterozygous loss-of-function mutations in positive effectors of the transforming growth factor-β (TGF-β) pathway. Using a mouse model of Loeys-Dietz syndrome (LDS) that carries a heterozygous kinase-inactivating mutation in TGF-β receptor I, we found that the effects of this mutation depend on the lineage of origin of vascular smooth muscle cells (VSMCs). Secondary heart field–derived (SHF-derived), but not neighboring cardiac neural crest–derived (CNC-derived), VSMCs showed impaired Smad2/3 activation in response to TGF-β, increased expression of angiotensin II (AngII) type 1 receptor (Agtr1a), enhanced responsiveness to AngII, and higher expression of TGF-β ligands. The preserved TGF-β signaling potential in CNC-derived VSMCs associated, in vivo, with increased Smad2/3 phosphorylation. CNC-, but not SHF-specific, deletion of Smad2 preserved aortic wall architecture and reduced aortic dilation in this mouse model of LDS. Taken together, these data suggest that aortic root aneurysm predisposition in this LDS mouse model depends both on defective Smad signaling in SHF-derived VSMCs and excessive Smad signaling in CNC-derived VSMCs. This work highlights the importance of considering the regional microenvironment and specifically lineage-dependent variation in the vulnerability to mutations in the development and testing of pathogenic models for aortic aneurysm.es
dc.description.versionVersión Publicadaes
dc.identifier.citationMacFarlane EG, Parker SJ, Shin JY, Kang BE, Ziegler SG, Creamer TJ, Bagirzadeh R, Bedja D, Chen Y, Calderon JF, Weissler K, Frischmeyer-Guerrerio PA, Lindsay ME, Habashi JP, Dietz HC. Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome. J Clin Invest. 2019 Feb 1;129(2):659-675. doi: 10.1172/JCI123547.es
dc.identifier.urihttps://doi.org/10.1172/JCI123547es
dc.identifier.urihttp://hdl.handle.net/11447/6246
dc.language.isoenes
dc.subjectVascular Biologyes
dc.subjectMonogenic diseaseses
dc.subjectMouse modelses
dc.subjectSignal transductiones
dc.titleLineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndromees
dc.typeArticlees
dcterms.sourceJournal of clinical investigationes

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