Single-cell analysis of salt-induced hypertensive mouse aortae reveals cellular heterogeneity and state changes

Abstract

Elevated blood pressure caused by excessive salt intake is common and associated with cardiovascular diseases in most countries. However, the composition and responses of vascular cells in the progression of hypertension have not been systematically described. We performed single-cell RNA sequencing on the aortic arch from C57BL/6J mice fed a chow/high-salt diet. We identified 19 distinct cell populations representing 12 lineages, including smooth muscle cells (SMCs), fibroblasts, endothelial cells (ECs), B cells, and T cells. During the progression of hypertension, the proportion of three SMC subpopulations, two EC subpopulations, and T cells increased. In two EC clusters, the expression of reactive oxygen species-related enzymes, collagen and contractility genes was upregulated. Gene set enrichment analysis showed that three SMC subsets underwent endothelial-to-mesenchymal transition. We also constructed intercellular networks and found more frequent cell communication among aortic cells in hypertension and that some signaling pathways were activated during hypertension. Finally, joint public genome-wide association study data and our single-cell RNA-sequencing data showed the expression of hypertension susceptibility genes in ECs, SMCs, and fibroblasts and revealed 21 genes involved in the initiation and development of high-salt-induced hypertension. In conclusion, our data illustrate the transcriptional landscape of vascular cells in the aorta associated with hypertension and reveal dramatic changes in cell composition and intercellular communication during the progression of hypertension.

DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice

“…Next, we assessed the composition of cells in the aorta as a result of DPP4 inhibition using singlecell RNA sequencing (scRNA-seq) and DPP4 Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) analyses (39). We identified 11 cell types defined by 21 clusters of aortic cells using cell type-specific markers for all major cell types as defined in the literature (40)(41)(42)(43) (Figure 8A, Supplemental Figure S7, and Supplemental Figure S8, A and B). We visualized total Dpp4 mRNA expression levels as well as the levels of DPP4 protein distribution on the cell surface in all cells (Figure 8, B and C).…”

A CXCL12 morphogen gradient uncovers lung endothelial heterogeneity and promotes distal vascular growth

“…These 3 populations have previously established physiological functions within the kidney. Similarly, the aorta is segregated into subpopulations that regulate different arterial responses at homeostasis and hypertensive states in humans and mice (Kalluri et al, 2019; Zhang et al, 2021). Similar findings exist in a study on the adult human pulmonary artery endothelium in health and disease.…”

Autoantibodies Targeting AT1- and ETA-Receptors Link Endothelial Proliferation and Coagulation via Ets-1 Transcription Factor

“…One such modern approach to identify how SRC-IgG differentially influence EC and vSMC would be single-cell sequencing. Two recent articles have thus investigated the relative impact of EC and vSMC in hypertension-induced vascular remodeling [ 43 , 44 ]. In a mouse model of salt-induced hypertension, Zhang et al showed that hypertensive vessels present increased smooth muscle cell populations, partly due to endothelial-to-mesenchymal cell transition [ 44 ].…”

“…Two recent articles have thus investigated the relative impact of EC and vSMC in hypertension-induced vascular remodeling [ 43 , 44 ]. In a mouse model of salt-induced hypertension, Zhang et al showed that hypertensive vessels present increased smooth muscle cell populations, partly due to endothelial-to-mesenchymal cell transition [ 44 ]. In a context of systemic sclerosis, single-cell sequencing was used to study immune cell heterogeneity between patients and healthy controls using skin samples [ 45 ], or whole endothelial cell genetic patterns in individuals with or without the disease [ 46 ].…”