Obesity accelerates endothelial-to-mesenchymal transition in adipose tissues of mice and humans

被引:2
作者
Chavkin, Nicholas W. [1 ,2 ]
Vippa, Tanvi [1 ]
Jung, Changhee [1 ]
McDonnell, Stephanie [2 ]
Hirschi, Karen K. [1 ,2 ,3 ]
Gokce, Noyan [4 ,5 ]
Walsh, Kenneth [1 ,6 ]
机构
[1] Univ Virginia, Sch Med, Robert M Berne Cardiovasc Res Ctr, Charlottesville, VA 22908 USA
[2] Univ Virginia, Sch Med, Dept Cell Biol, Charlottesville, VA 22902 USA
[3] Yale Univ, Yale Cardiovasc Res Ctr, Sch Med, Dept Med, New Haven, CT USA
[4] Boston Univ, Sch Med, Dept Med, Boston, MA USA
[5] Boston Univ, Whitaker Cardiovasc Inst, Sch Med, Boston, MA USA
[6] Univ Virginia, Hematovascular Biol Ctr, Sch Med, Charlottesville, VA 22903 USA
来源
FRONTIERS IN CARDIOVASCULAR MEDICINE | 2023年 / 10卷
基金
美国国家卫生研究院;
关键词
endothelial-to-mesenchymal transition; obesity; adipose; endothelium; aging; vascular biology; CARDIOVASCULAR-DISEASE; INFLAMMATION; CELL; RAREFACTION; DYSFUNCTION; FIBROSIS; CONTRIBUTES; ACTIVATION; MECHANISMS; HEALTH;
D O I
10.3389/fcvm.2023.1264479
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
IntroductionVascular dysfunction and chronic inflammation are characteristics of obesity-induced adipose tissue dysfunction. Proinflammatory cytokines can drive an endothelial-to-mesenchymal transition (EndoMT), where endothelial cells undergo a phenotypic switch to mesenchymal-like cells that are pro-inflammatory and pro-fibrotic. In this study, we sought to determine whether obesity can promote EndoMT in adipose tissue.MethodsMice in which endothelial cells are lineage-traced with eYFP were fed a high-fat/high-sucrose (HF/HS) or Control diet for 13, 26, and 52 weeks, and EndoMT was assessed in adipose tissue depots as percentage of CD45-CD31-Acta2+ mesenchymal-like cells that were eYFP +. EndoMT was also assessed in human adipose endothelial cells through cell culture assays and by the analysis of single cell RNA sequencing datasets obtained from the visceral adipose tissues of obese individuals.ResultsQuantification by flow cytometry showed that mice fed a HF/HS diet display a time-dependent increase in EndoMT over Control diet in subcutaneous adipose tissue (+3.0%, +2.6-fold at 13 weeks; +10.6%, +3.2-fold at 26 weeks; +11.8%, +2.9-fold at 52 weeks) and visceral adipose tissue (+5.5%, +2.3-fold at 13 weeks; +20.7%, +4.3-fold at 26 weeks; +25.7%, +4.8-fold at 52 weeks). Transcriptomic analysis revealed that EndoMT cells in visceral adipose tissue have enriched expression of genes associated with inflammatory and TGF beta signaling pathways. Human adipose-derived microvascular endothelial cells cultured with TGF-beta 1, IFN-gamma, and TNF-alpha exhibited a similar upregulation of EndoMT markers and induction of inflammatory response pathways. Analysis of single cell RNA sequencing datasets from visceral adipose tissue of obese patients revealed a nascent EndoMT sub-cluster of endothelial cells with reduced PECAM1 and increased ACTA2 expression, which was also enriched for inflammatory signaling genes and other genes associated with EndoMT.DiscussionThese experimental and clinical findings show that chronic obesity can accelerate EndoMT in adipose tissue. We speculate that EndoMT is a feature of adipose tissue dysfunction that contributes to local inflammation and the systemic metabolic effects of obesity..
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