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Introduction Aneurysms are focal dilatations in the wall of an artery that are often asymptomatic until dissection (tear) or rupture occurs (1, 2). Thoracic aortic aneurysms occur in all age [...], The 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-[beta] (TGF-[beta]) pathway. Using a mouse model of Loeys-Dietz syndrome (LDS) that carries a heterozygous kinase-inactivating mutation in TGF-[beta] 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-[beta], increased expression of angiotensin II (AngII) type 1 receptor (Agtr1a), enhanced responsiveness to AngII, and higher expression of TGF-[beta] ligands. The preserved TGF-[beta] 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.

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Competing Interests: Dr Zawatsky has received personal fees from Color Genomics to Chair the NIH All of Us Genetic Counseling Resource Advisory and Advocacy Board, Atria, Harvard Catalyst. Dr Fifer has received research grants from Bristol Myers Squibb and 10.13039/100004336Novartis; and has received personal fees from Viz.ai, Bristol Myers Squibb, Cytokinetics, and Edgewise. Dr Tower-Rader has received research grants from Bristol Myers Squibb and 10.13039/100014941Cytokinetics. Dr Green has received personal fees from Allelica, Atria, Fabric, Genomic Life, and Juniper Genomics; and is co-founder of Genome Medical and Nurture Genomics. Dr Natarajan has received research grants from Allelica, 10.13039/100002429Amgen, 10.13039/100017567Apple, 10.13039/100008497Boston Scientific, 10.13039/100004328Genentech/10.13039/100004337Roche, and 10.13039/100004336Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, and Novartis; scientific advisory board membership of Esperion Therapeutics, Preciseli, TenSixteen Bio, and Tourmaline Bio; scientific co-founder of TenSixteen Bio; holds equity in MyOme, Preciseli, and TenSixteen Bio; and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.