Aortic heterogeneity across segments and under high fat/salt/glucose conditions at the single-cell level

Abstract

The aorta, with ascending, arch, thoracic and abdominal segments, responds to the heartbeat, senses metabolites and distributes blood to all parts of the body. However, the heterogeneity across aortic segments and how metabolic pathologies change it are not known. Here, a total of 216 612 individual cells from the ascending aorta, aortic arch, and thoracic and abdominal segments of mouse aortas under normal conditions or with high blood glucose levels, high dietary salt, or high fat intake were profiled using single-cell RNA sequencing. We generated a compendium of 10 distinct cell types, mainly endothelial (EC), smooth muscle (SMC), stromal and immune cells. The distributions of the different cells and their intercommunication were influenced by the hemodynamic microenvironment across anatomical segments, and the spatial heterogeneity of ECs and SMCs may contribute to differential vascular dilation and constriction that were measured by wire myography. Importantly, the composition of aortic cells, their gene expression profiles and their regulatory intercellular networks broadly changed in response to high fat/salt/glucose conditions. Notably, the abdominal aorta showed the most dramatic changes in cellular composition, particularly involving ECs, fibroblasts and myeloid cells with cardiovascular risk factor-related regulons and gene expression networks. Our study elucidates the nature and range of aortic cell diversity, with implications for the treatment of metabolic pathologies.

Single-cell transcriptome analysis reveals cellular heterogeneity in the ascending aortas of normal and high-fat diet-fed mice

“…Our study showed that there are 5 subtypes of vascular SMCs in the ascending aorta: synthetic (SMC_1), contractile (SMC_2), fibroblast-like (SMC_3), and inflammatory (SMC_4 and SMC_5) SMCs. The presence of synthetic, contractile, and fibroblast-like subpopulations is consistent with previous reports 15 , 16 , 37 . SMC_1 accounted for the highest proportion and expressed genes involved in cell proliferation and migration, but it expressed low levels of contractile genes.…”

“…Qualified aortic cell suspensions were loaded onto a Single-Cell Instrument (10x Genomics GemCode Technology, CA) to generate single-cell Gel beads in EMulsion (GEMs, Single Cell 3′ Library and Gel Bead Kit V2 [10x Genomics]). The sequencing protocols have been described in a previous report 15 . Briefly, the single-cell suspension, reagents, gel beads, and partitioning oil were loaded onto 10x Chromium Chip B. Single-cell RNA was barcoded through reverse transcription in individual GEMs.…”

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

“…These subpopulations have gene expression patterns that are suggestive of functional specialization (e.g. angiogenesis, inflammatory responses, vasomotor control, extracellular matrix production) and are modulated by diet and blood pressure [83][84][85]. We have not addressed the mechanisms responsible for promoting altered endothelial cell clustering in the present study.…”

Single-Cell Transcriptomics Reveals the Cellular Heterogeneity of Cardiovascular Diseases

“…The arrival of single-cell transcriptomics is now providing unprecedented opportunities to discover new immune cell subpopulations. Eleven immune cell subpopulations are identified in the aorta of atherosclerotic mice (13); however, only five or less subtypes are identified in healthy mice (14,15), suggesting a high degree of immune cell heterogeneity in the diseased vasculature. Different species, tissue, disease,…”

“…The former expresses typical contractile proteins αSMA, MYH11, SM22α, and CNN1. When stimulated by injury or inflammation, VSMCs downregulate the expression of contractile genes, increase extracellular matrix (ECM) synthesis, and enhance secretion, migration, and proliferation (69), a motility-associated VTN high VSMCs has been identified as an intermediate switching type (15). Loss of VSMC characteristic is a key factor in vascular diseases such as atherosclerosis, aortic aneurysm, pulmonary hypertension, and restenosis (70).…”