Lymphatic ERG Governs Junctional Plasticity and Fluid Clearance via an EDNRB Signaling Axis in Pulmonary Fibrosis

Lymphatic endothelial cells (LECs) play a critical role in maintaining fluid balance and macromolecular clearance within the lungs. However, the specific mechanisms governing lymphatic vessel function during chronic fibroproliferative lung injury, such as pulmonary fibrosis, remain unclear. In this study, researchers identified a key transcription factor, ERG, that governs junctional plasticity and fluid drainage in pulmonary fibrosis.

Human idiopathic pulmonary fibrosis (IPF) lungs exhibit significantly reduced ERG expression in lymphatic endothelial cells. To investigate the impact of ERG loss, the researchers conducted a murine model of bleomycin-induced pulmonary fibrosis. They observed that lineage-specific deletion of Erg in murine LECs (Erg-CKO) provided robust protection against the disease. This protection manifested as significantly reduced acute inflammation, decreased edema, and preserved pulmonary compliance.

The researchers further explored the underlying mechanisms and discovered that loss of ERG led to enhanced lymphatic drainage capacity in vivo. Transcriptomic profiling of isolated LECs revealed that ERG deficiency activated actomyosin contractile pathways and upregulated Endothelin Receptor Type B (Ednrb). These changes in gene expression drove junctional remodeling from continuous zippers to discontinuous button-like configurations, facilitating increased interstitial fluid entry.

Interestingly, pharmacological blockade of Ednrb with BQ-788 abolished the observed junctional reorganization, eliminated the enhanced lymphatic drainage, and completely reversed the anti-fibrotic protection conferred by the Erg-CKO mice. These findings collectively identify an endothelial ERG-Ednrb regulatory axis that controls lymphatic junctional architecture and demonstrates that promoting lymphatic clearance through endothelial junctional remodeling presents a viable therapeutic strategy for fibrotic vascular remodeling in pulmonary fibrosis.