What question did this study set out to answer?

This research aims to explore how macrophages contribute to the progression of chronic thromboembolic pulmonary hypertension (CTEPH) through specific signaling pathways.

May 20, 2026

D106-08 Macrophages Orchestrate Chronic Thromboembolic Pulmonary Hypertension Progression From Proximal Thrombosis to Distal Fibrosis Through the Fn1-cd44-gpnmb Axis

Key Points

This research aims to explore how macrophages contribute to the progression of chronic thromboembolic pulmonary hypertension (CTEPH) through specific signaling pathways.
Integrated analysis of 10x Genomics spatial transcriptomics and single-cell RNA sequencing on lesions from pulmonary endarterectomy specimens.
Mapped cellular ecosystems at proximal, mid, and distal anatomical sites to determine macrophage behavior and interaction with signaling axes.
Proximal and mid lesions showed 46.04% and 46.67% macrophage infiltration, respectively, while distal lesions had 35.10% mural cells and 24.50% fibroblasts, indicating advanced fibrosis.
Identification of the FN1-CD44-GPNMB signaling axis as central to CTEPH progression, linking inflammation to fibrosis.

Abstract

Abstract Rationale Chronic thromboembolic pulmonary hypertension (CTEPH) progression is driven by pathological transitions from proximal thrombus organisation to distal vascular remodelling, yet the spatial distribution and regulatory mechanisms of macrophages across these anatomical compartments remain poorly defined. Methods Through integrated analysis of 10x Genomics spatial transcriptomics and single-cell RNA sequencing performed on proximal (elastic arteries), mid (transitional), and distal (muscular arterioles) lesions from pulmonary endarterectomy specimens, we mapped a spatial cellular ecosystem revealing a striking pathological gradient along the proximo-distal axis. Results While proximal and mid lesions featured an inflammatory microenvironment with abundant macrophage infiltration (46.04% and 46.67%, respectively), distal lesions were dominated by mural cells (35.10%) and fibroblasts (24.50%), indicative of advanced microvasculopathy and fibrosis. A novel signaling axis comprising Fibronectin 1 (FN1), CD44, and Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) was identified as central to disease progression. This axis consisted of two key components: 1) stromal FN1 promoted macrophage recruitment/retention via CD44, and 2) GPNMB (highly expressed in APOC1+ macrophages) interacted with CD44 to drive lipid metabolic reprogramming and accumulation. Consequently, the GPNMB-CD44 interaction linked proximal inflammation to a pro-fibrotic state, ultimately promoting distal vascular remodeling. Conclusions Our study unveils the spatial heterogeneity of macrophages in CTEPH and delineates a pivotal role for the FN1-CD44-GPNMB axis in driving disease progression, providing a new conceptual framework and potential therapeutic targets for intervention. This abstract is funded by: This study was supported by Natural Science Foundation of Fujian Province (2023J01092), National Natural Science Foundation of China (No.82470043), Major Scientific Research Program for Young and Middle-aged Health Professionals of Fujian Province (No.2023ZQNZD006).

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Cite This Study

Yan et al. (Fri,) studied this question.

synapsesocial.com/papers/6a0d5025f03e14405aa9bca1 https://doi.org/https://doi.org/10.1093/ajrccm/aamag162.5889

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