Molecular Changes Implicate Angiogenesis and Arterial Remodeling in Systemic Sclerosis-Associated and Idiopathic Pulmonary Hypertension.

IF 7.4 1区 医学 Q1 HEMATOLOGY
Yuechen Zhou, Tracy Tabib, Mengqi Huang, Ke Yuan, Yunhye Kim, Christina Morse, John Sembrat, Eleanor Valenzi, Robert Lafyatis
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引用次数: 0

Abstract

Background: Pulmonary hypertension (PH) is a common complication of systemic sclerosis (SSc) and a leading cause of mortality among patients with this disease. PH can also occur as an idiopathic condition (idiopathic pulmonary arterial hypertension). Investigation of transcriptomic alterations in vascular populations is critical to elucidating cellular mechanisms underlying pathobiology of SSc-associated and idiopathic PH.

Methods: We analyzed single-cell RNA sequencing profiles of endothelial and perivascular mesenchymal populations from explanted lung tissue of patients with SSc-associated PH (n=16), idiopathic pulmonary arterial hypertension (n=3), and healthy controls (n=15). Findings were validated by immunofluorescence staining of explanted human lung tissue.

Results: Three disease-associated endothelial populations emerged. Two angiogenic endothelial cell (EC) subtypes markedly expanded in SSc-associated PH lungs: tip ECs expressing canonical tip markers PGF and APLN and phalanx ECs expressing genes associated with vascular development, endothelial barrier integrity, and Notch signaling. Gene regulatory network analysis suggested enrichment of Smad1 (SMAD family member 1) and PPAR-γ (peroxisome proliferator-activated receptor-γ) regulon activities in these 2 populations, respectively. Mapping of potential ligand-receptor interactions highlighted Notch, apelin-APJ (apelin receptor), and angiopoietin-Tie (tyrosine kinase with immunoglobulin-like and EGF-like domains 1) signaling pathways between angiogenic ECs and perivascular cells. Transitional cells, expressing both endothelial and pericyte/smooth muscle cell markers, provided evidence for the presence of endothelial-to-mesenchymal transition. Transcriptional programs associated with arterial endothelial dysfunction implicated VEGF-A (vascular endothelial growth factor-A), TGF-β1 (transforming growth factor beta-1), angiotensin, and TNFSF12 (tumor necrosis factor ligand superfamily member 12)/TWEAK (TNF-related weak inducer of apoptosis) in the injury/remodeling phenotype of PH arterial ECs.

Conclusions: These data provide high-resolution insights into the complexity and plasticity of the pulmonary endothelium in SSc-associated PH and idiopathic pulmonary arterial hypertension and provide direct molecular insights into soluble mediators and transcription factors driving PH vasculopathy.

系统性硬化症相关肺动脉高压和特发性肺动脉高压中血管生成和动脉重塑的分子变化。
背景:肺动脉高压(PH)是系统性硬化症(SSc)的常见并发症,也是导致该病患者死亡的主要原因。肺动脉高压也可能是一种特发性疾病(特发性肺动脉高压)。研究血管群体的转录组变化对于阐明 SSc 相关性 PH 和特发性 PH 的病理生物学细胞机制至关重要:我们分析了SSc相关性PH患者(16例)、特发性肺动脉高压患者(3例)和健康对照组(15例)肺组织中内皮细胞和血管周围间充质细胞群的单细胞RNA测序图谱。免疫荧光染色法验证了对人体肺组织的研究结果:结果:出现了三种与疾病相关的内皮细胞群。两种血管生成内皮细胞(EC)亚型在SSc相关的PH肺中明显扩大:表达典型尖端标记物PGF和APLN的尖端EC和表达与血管发育、内皮屏障完整性和Notch信号转导相关基因的趾状EC。基因调控网络分析表明,Smad1 和 PPAR-γ(过氧化物酶体增殖激活受体-γ)调控子的活性分别在这两个群体中得到了丰富。潜在配体-受体相互作用图谱突出显示了血管生成细胞和血管周围细胞之间的Notch、apelin-APJ和血管生成素-Tie信号通路。表达内皮细胞和周细胞/平滑肌细胞标记的过渡细胞为内皮细胞向间质转化的存在提供了证据。与动脉内皮功能障碍相关的转录程序表明,VEGF-A(血管内皮生长因子-A)、TGF-β1、血管紧张素和 TNFSF12/TWEAK 与 PH 动脉 EC 的损伤/重塑表型有关:这些数据提供了关于 SSc 相关 PH 和特发性肺动脉高压中肺动脉内皮复杂性和可塑性的高分辨率见解,并提供了关于驱动 PH 血管病变的可溶性介质和转录因子的直接分子见解。
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来源期刊
CiteScore
15.60
自引率
2.30%
发文量
337
审稿时长
2-4 weeks
期刊介绍: The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA). The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.
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