Analysis of Combined Transcriptomes Identifies Gene Modules that Differentially Respond to Pathogenic Stimulation of Vascular Smooth Muscle and Endothelial Cells

Xiaokang Pan,K Craig Kent,Lian-Wang Guo,Mengxue Zhang,Tiezheng Yuan,Bowen Wang

doi:10.1038/s41598-017-18675-2

Abstract

Smooth muscle cells (SMCs) and endothelial cells (ECs) are vital cell types composing the vascular medial wall and the atheroprotective inner lining, respectively. Current treatments for cardiovascular disease inhibit SMC hyperplasia but compromise EC integrity, predisposing patients to thrombosis. Therapeutics targeting SMCs without collateral damage to ECs are highly desirable. However, differential (SMC versus EC) disease-associated regulations remain poorly defined. We conducted RNA-seq experiments to investigate SMC-versus-EC differential transcriptomic dynamics, following treatment of human primary SMCs and ECs with TNFα or IL-1β, both established inducers of SMC hyperplasia and EC dysfunction. As revealed by combined SMC/EC transcriptomes, after TNFα or IL-1β induction, 174 and 213 genes respectively showed greater up-regulation in SMCs than in ECs (SMC-enriched), while 117 and 138 genes showed greater up-regulation in ECs over SMCs (EC-enriched). Analysis of gene interaction networks identified central genes shared in the two SMC-enriched gene sets, and a distinct group of central genes common in the two EC-enriched gene sets. Significantly, four gene modules (subnetworks) were identified from these central genes, including SMC-enriched JUN and FYN modules and EC-enriched SMAD3 and XPO1 modules. These modules may inform potential intervention targets for selective blockage of SMC hyperplasia without endothelial damage.

Highlights

Smooth muscle cells (SMCs) and endothelial cells (ECs) are vital cell types composing the vascular medial wall and the atheroprotective inner lining, respectively
Using criteria based on this gene module definition, we identified two modules shared in SMC-enriched GIN1 and GIN2 and two common modules in EC-enriched GIN3 and GIN4
While previous cell physiology studies showed similar outcomes of TNFα and IL-1β treatments[27], our results indicate that between TNFα and IL-1β experiments of the same SMC or EC cell type, large overlap exists in pathways, gene ontology (GO) terms, gene sets (GSs), Gene interaction network (GIN), hubs, and bottlenecks

Summary

Introduction

Smooth muscle cells (SMCs) and endothelial cells (ECs) are vital cell types composing the vascular medial wall and the atheroprotective inner lining, respectively. Smooth muscle cells (SMCs) and endothelial cells (ECs) are major cell types in the vascular wall constituting the media layer and the inner lining of endothelium, respectively Disturbation of their homeostasis due to surgical interventions often leads to failure of those treatments. Because of a close vicinity in the vascular wall, SMCs and ECs are exposed to similar environments of pathophysiological stimuli, yet their responses are drastically different These differential responses profoundly influence the outcomes of surgical (and pharmacological) interventions using drug-eluting stents. The only therapeutics applied in drug-eluting stents are sirolimus (or analogs) and paclitaxel[6,7,8,9] While these anti-proliferative drugs are effective inhibitors of SMC hyperplasia, they are toxic to ECs and retard reendothelialization, predisposing patients to thrombosis and restenosis[10]. Genomewide investigations of transcriptomes or pathways differentially regulated in SMCs versus ECs in response to pathogenic stimuli are extremely rare

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