Intrinsic GATA4 expression sensitizes the aortic root to dilation in a Loeys-Dietz syndrome mouse model

Emily E Bramel; Wendy A Espinoza Camejo; Tyler J Creamer; Leda Restrepo; Muzna Saqib; Rustam Bagirzadeh; Anthony Zeng; Jacob T Mitchell; Genevieve L Stein-O'Brien; Albert J Pedroza; Michael P Fischbein; Harry C Dietz; Elena Gallo MacFarlane

doi:10.1038/s44161-024-00562-5

Intrinsic GATA4 expression sensitizes the aortic root to dilation in a Loeys-Dietz syndrome mouse model

Nat Cardiovasc Res. 2024 Nov 20. doi: 10.1038/s44161-024-00562-5. Online ahead of print.

Authors

Emily E Bramel^{1

2}, Wendy A Espinoza Camejo^{1

2}, Tyler J Creamer^{1

3}, Leda Restrepo¹, Muzna Saqib¹, Rustam Bagirzadeh¹, Anthony Zeng¹, Jacob T Mitchell^{1

2}, Genevieve L Stein-O'Brien^{1

4}, Albert J Pedroza⁵, Michael P Fischbein⁵, Harry C Dietz¹, Elena Gallo MacFarlane^{6

7}

Affiliations

¹ McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Predoctoral Training in Human Genetics and Genomics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
⁶ McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. egallo1@jhmi.edu.
⁷ Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. egallo1@jhmi.edu.

PMID: 39567770
DOI: 10.1038/s44161-024-00562-5

Abstract

Loeys-Dietz syndrome (LDS) is a connective tissue disorder caused by mutations that decrease transforming growth factor-β signaling. LDS-causing mutations increase the risk of aneurysm throughout the arterial tree, yet the aortic root is a site of heightened susceptibility. Here we investigate the heterogeneity of vascular smooth muscle cells (VSMCs) in the aorta of Tgfbr1^M318R/+ LDS mice by single-cell transcriptomics to identify molecular determinants of this vulnerability. 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 single-cell RNA sequencing 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 transforming growth factor-β signaling.

Abstract

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