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Endothelial GDF15 deficiency enhances barrier function and mitigates pulmonary fibrosis

Kristen Raffensperger,¹ Marta Bueno,² Brian J. Philips,³ Megan Miller,³ Máté Katona,³ Shuai Yuan,³ Adriana Estrada-Bernal,² Byron Chuan,² Pavan Suresh,² Stephanie Taiclet,⁴ Scott Hahn,⁴ Yingze Zhang,² Jonathan K. Alder,² Seyed Mehdi Nouraie,² Daniel J. Kass,¹ Oliver Eickelberg,² and Adam C. Straub³

Published April 23, 2026 - More info

Pulmonary fibrosis is frequently accompanied by pulmonary hypertension, which can occur disproportionate to the extent of fibrosis, suggesting a fibrosis-independent vascular remodeling process. Here, we demonstrated that plasma growth differentiation factor 15 (GDF15) is elevated across diverse fibrotic lung disease subtypes and correlates with markers of elevated right heart pressures, but not pulmonary function indices, indicating a possible link to endothelial cell dysfunction. To investigate the import of endothelial GDF15 as a modifier of lung fibrosis pathogenesis, we generated endothelial cell-specific Gdf15 knockout mice, which showed protection from bleomycin-induced lung injury and fibrosis, with preserved lung function. RNA sequencing of human pulmonary microvascular endothelial cells revealed altered expression of barrier-regulatory genes in GDF15-deficient endothelial cells compared to controls. Functional studies confirmed that GDF15 knockdown attenuates thrombin-induced barrier disruption by reducing cytosolic Ca²⁺ responses. Together, these findings implicate endothelial GDF15 as a modifier of vascular permeability and Ca²⁺ signaling, and a contributor to lung injury and fibrosis.

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