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

TL;DR

This study finds that Gata4 expression in vascular smooth muscle cells makes the aortic root more vulnerable to dilation in a mouse model of Loeys-Dietz syndrome.

Contribution

The study identifies Gata4 as a novel intrinsic factor that increases aortic root vulnerability in Loeys-Dietz syndrome.

Findings

LDS VSMCs show reduced extracellular matrix-receptor components and increased stress/inflammatory pathways.

Gata4-expressing VSMCs in the aortic root have a less differentiated, proinflammatory profile.

Deleting Gata4 in VSMCs reduces aortic root dilation in LDS mice.

Abstract

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 Tgfbr1M318R/+ 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.

Figures