Chavkin Nicholas W, Vippa Tanvi, Jung Changhee, McDonnell Stephanie, Hirschi Karen K, Gokce Noyan, Walsh Kenneth
Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, United States.
Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, United States.
Front Cardiovasc Med. 2023 Sep 19;10:1264479. doi: 10.3389/fcvm.2023.1264479. eCollection 2023.
Vascular 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.
Mice 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 CD45CD31Acta2 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.
Quantification 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 TGFβ signaling pathways. Human adipose-derived microvascular endothelial cells cultured with TGF-β1, IFN-γ, and TNF-α 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 and increased expression, which was also enriched for inflammatory signaling genes and other genes associated with EndoMT.
These 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..
血管功能障碍和慢性炎症是肥胖诱导的脂肪组织功能障碍的特征。促炎细胞因子可驱动内皮-间充质转化（EndoMT），即内皮细胞经历表型转变为促炎和促纤维化的间充质样细胞。在本研究中，我们试图确定肥胖是否能促进脂肪组织中的EndoMT。
用eYFP对内皮细胞进行谱系追踪的小鼠喂食高脂/高糖（HF/HS）或对照饮食13、26和52周，并在脂肪组织库中评估EndoMT，以eYFP+的CD45-CD31+Acta2+间充质样细胞的百分比表示。还通过细胞培养试验以及对从肥胖个体的内脏脂肪组织获得的单细胞RNA测序数据集的分析，在人脂肪内皮细胞中评估EndoMT。
流式细胞术定量分析显示，喂食HF/HS饮食的小鼠与对照饮食相比，皮下脂肪组织中EndoMT呈时间依赖性增加（13周时增加3.0%，增加2.6倍；26周时增加10.6%，增加3.2倍；52周时增加11.8%，增加2.9倍），内脏脂肪组织中也是如此（13周时增加5.5%，增加2.3倍；26周时增加20.7%，增加4.3倍；52周时增加25.7%，增加4.8倍）。转录组分析表明，内脏脂肪组织中的EndoMT细胞中与炎症和TGFβ信号通路相关的基因表达富集。用TGF-β1、IFN-γ和TNF-α培养的人脂肪来源的微血管内皮细胞表现出EndoMT标志物的类似上调和炎症反应途径的诱导。对肥胖患者内脏脂肪组织的单细胞RNA测序数据集的分析揭示了一个新的内皮细胞EndoMT亚群，其表达降低而表达增加，该亚群也富含炎症信号基因和与EndoMT相关的其他基因。
这些实验和临床发现表明，慢性肥胖可加速脂肪组织中的EndoMT。我们推测EndoMT是脂肪组织功能障碍的一个特征，它导致局部炎症和肥胖的全身代谢效应。
