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FOSL2 binding to enhancer elements regulates endothelial cell state in systemic sclerosis pulmonary vascular disease

ABSTRACT: Systemic Sclerosis (SSc) is characterized by fibrosis and vasculopathy affecting the skin and internal organs, leading to multi-organ dysfunction. Injury of microvascular ECs in SSc impairs blood flow and causes tissue ischemia, leading to vascular complications such as Raynaud’s, digital ulcers, and pulmonary hypertension (PH). PH in SSc presents as group 1 pulmonary arterial hypertension (PAH) or as group 3 PH related to hypoxia and interstitial lung disease (ILD), both major causes of mortality. Analysis of multiome data from SSc ILD-PH lungs inferred transcription factors regulating EC phenotype, including FOSL2. Overexpression of FOSL2 in transgenic mice (Fosl2tg) leads to vascular changes mirroring human SSc-PH, such as intimal thickening and fibrosis. ScRNA-seq analysis of altered EC gene expression in the Fosl2tg mice showed strong overlap with altered EC gene in SSc-ILD-PH. Overlapping as well as discrete EC gene expression in SuGene/hxpoxia- and hypoxia-treated mice suggested that FOSL2 regulates both hypoxia-dependent and independent pathways in Fosl2tg mice and SSc-ILD-PH. The deep learning model, ChromBPNet, inferred increased AP-1 binding at base pair resolution in SSc-ILDPH ECs and binding to the same motifs was found upon FOSL2 overexpression in primary vascular ECs, highlighting FOSL2’s key role in driving the pathological changes seen in SSc-ILDPH.

ORGANISM(S): Mus musculus

PROVIDER: GSE314055 | GEO | 2026/02/20

REPOSITORIES: GEO

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Project description:Dysfunction of pulmonary arterial endothelial cells (PAECs) is associated with the development and progression of vascular pathology. However, it remains unknown how pulmonary hypertension (PH) affects cellular composition and transcriptomic profile of pulmonary endothelium. Here, we have undertaken a single-cell, compartment specific approach to characterise alterations in PAECs associated with two different types of PH, i.e., pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with pulmonary fibrosis (PHPF). Our unbiased analysis showed that endothelium of medium / small caliber pulmonary arteries is composed of three subsets of endothelial cells (ECs). The analysis of healthy and PH endothelium revealed that the three populations are persistently represented in remodelled arteries. Additionally, an exploratory analysis of human aorta (AO) and coronary arteries (CA) endothelium revealed that, although similar gene expression patterns were noticeable, PAECs subpopulations proportions differs significantly from pulmonary arteries (PA) endothelium. To address whether EC heterogeneity is a prime feature of human endothelium, we also performed a similar analysis in a murine model of hypoxia, revealing that similar EC populations were evident in this animal model. Comparative analysis of EC subpopulations in healthy and PH EC identified a common genetic deregulation accompanying vascular remodelling. Even though murine EC displayed some similarities with human EC subpopulations, the intense re-programming associated with hypoxia associated vascular remodelling displayed significant differences compared to the human disease. Finally, in depth comparative analysis of PAH and PHPF EC highlighted the development of disease-specific transcriptomic alterations in the three populations. Therefore, characterisation of transcriptomic differences in the endothelial bed of PAH and PHPF patients can facilitate identification of novel, disease-specific therapeutic targets.

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FOSL2 binding to enhancer elements regulates endothelial cell state in systemic sclerosis pulmonary vascular disease

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