Deciphering endothelial heterogeneity in health and disease at single cell resolution: progress and perspectives

Endothelial cells (ECs) constitute the inner lining of vascular beds in mammals and are crucial for homeostatic regulation of blood vessel physiology, but also play a key role in pathogenesis of many diseases, thereby representing realistic therapeutic targets. However, it has become evident that ECs are heterogeneous, encompassing several subtypes with distinct functions, which makes EC targeting and modulation in the disease-context challenging. The rise of the new single cell era has led to an emergence of studies aimed at interrogating transcriptome diversity along the vascular tree, and has revolutionized our understanding of EC heterogeneity from both a physiological and pathophysiological context. Here, we discuss recent landmark studies aimed at teasing apart the heterogeneous nature of ECs. We cover driving (epi)genetic, transcriptomic and metabolic forces underlying EC heterogeneity in health and disease, as well as current strategies used to combat disease-enriched EC phenotypes, and propose strategies to transcend largely descriptive heterogeneity towards prioritization and functional validation of therapeutically targetable drivers of EC diversity. Lastly, we provide an overview of the most recent advances and hurdles in single EC OMICs

Investigating murine endothelial cell injury in pulmonary arterial hypertension using single-cell RNA sequencing

Endothelial cells (ECs) are highly heterogenous across different organs and within the vascular bed, in both health and disease. However, EC heterogeneity has not been extensively dissected in the context of pulmonary arterial hypertension (PAH). It is a rare and progressive disease characterised by remodelling of the distal pulmonary vasculature. Using an EC lineage-tracing mouse model and single-cell RNA-sequencing (scRNA-seq), I first investigated how enriched mouse ECs respond to Sugen 5416/Hypoxia-induced (SuHx) PAH. Globally, ECs adopt an immunophenotype in PAH, with upregulation of genes relating to the major histocompatibility class II (MHC-II) complex. The strongest upregulation is observed in Artery and one of the two capillary ECs (Capillary A/gCap). The other capillary EC cluster (Capillary B/aerocyte) had a distinct response to PAH, with upregulation of genes regulating apoptosis, migration, and angiogenesis. Comparison with whole-lung scRNA-seq in rat and human PAH identified several candidate genes conserved across all species. Following this, I further examined heterogeneity within Artery and Capillary A ECs, the pulmonary vasculature predominantly affected in PAH. Artery ECs can be subdivided into Proximal and Distal Artery ECs, with both groups having distinct biomarkers. In PAH, a loss of Proximal Artery EC identity and a gain in Distal Artery EC identity is observed. As for Capillary A ECs, three subpopulations were identified. In Control, two of these subclusters (CapillaryA_0, CapillaryA_1) were marked by high expression of Distal Artery markers, and low expression of Proximal Artery markers, whilst the reverse was true for the third CapillaryA_2 subcluster. There was also significantly more CapillaryA_2 ECs in PAH. Differential gene expression analysis found some genes uniquely upregulated in each CapillaryA subcluster: senescence-associated genes in CapillaryA_0 (Cd9, H3f3b, Neat1), signalling genes in CapillaryA_1 (Rab5a, Slc6a6, Tmem252), and both inflammatory (H2-Q4, Irgm1, Tgtp2) and angiogenesis regulatory genes (Cldn5, Cxcl12, Esam, Rhoj) in CapillaryA_2. Overall, this work has revealed in high-resolution, how ECs in different vascular beds distinctly respond to PAH

Internet tham khảo toàn diện = The Internet Complete Reference

768 tr. ; 24 cm

Single-cell RNA sequencing profiling of murine endothelial cells in Pulmonary Arterial Hypertension

## Access ## This dataset is held in the Edinburgh DataVault, directly accessible only to authorised University of Edinburgh staff. External users may request access to a copy of the data by contacting the Principal Investigator, Contact Person or Data Manager named on this page. University of Edinburgh users who wish to have direct access should consult the information about retrieving data from the DataVault at: https://www.ed.ac.uk/is/research-support/datavault.This vault contains the raw and processed data associated with the publication Rodor et al, Cardiovascular Research 2022. We carried out single-cell RNA sequencing (scRNA-seq) of lung ECs isolated from an EC lineage-tracing mouse model in Control and SU5416/hypoxia-induced PAH conditions. Data from the animal work, single-cell and bulk RNA-sequencing, and in vitro experiments have been deposited in this vault. Additionally, this vault also contains the processed data of publicly available human (PMID: 32166015) and rat (PMID: 33021809) whole-lung scRNA-seq data in PAH. Associated publication: https://doi.org/10.1093/cvr/cvab29