Intrinsic Gata4 expression sensitizes the aortic root to dilation in a Loeys-Dietz syndrome mouse model.

Autor:	Bramel EE; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Predoctoral Training in Human Genetics and Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Camejo WAE; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Predoctoral Training in Human Genetics and Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Creamer TJ; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Restrepo L; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Saqib M; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Bagirzadeh R; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Zeng A; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Mitchell JT; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Predoctoral Training in Human Genetics and Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Stein-O'Brien GL; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Pedroza AJ; Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, USA., Fischbein MP; Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, USA., Dietz HC; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., MacFarlane EG; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 Jun 05. Date of Electronic Publication: 2024 Jun 05.
DOI:	10.21203/rs.3.rs-4420617/v1
Abstrakt:	Loeys-Dietz syndrome (LDS) is an aneurysm disorder caused by mutations that decrease transforming growth factor-β (TGF-β) signaling. Although aneurysms develop throughout the arterial tree, the aortic root is a site of heightened risk. To identify molecular determinants of this vulnerability, we investigated the heterogeneity of vascular smooth muscle cells (VSMCs) in the aorta of Tgfbr1 M318R /+ LDS mice by single cell and spatial transcriptomics. Reduced expression of components of the extracellular matrix-receptor apparatus and upregulation of stress and inflammatory pathways were observed in all LDS VSMCs. However, regardless of genotype, a subset of Gata4 -expressing VSMCs predominantly located in the aortic root intrinsically displayed a less differentiated, proinflammatory profile. A similar population was also identified among aortic VSMCs in a human scRNAseq dataset. Postnatal VSMC-specific Gata4 deletion reduced aortic root dilation in LDS mice, suggesting that this factor sensitizes the aortic root to the effects of impaired TGF-β signaling. Competing Interests: Additional Declarations: There is NO Competing Interest. Conflict of interest statement The authors have declared that no conflict of interest exists.
Databáze:	MEDLINE
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