Endothelial GDF15 deficiency enhances barrier function and mitigates pulmonary fibrosis

Area of Science:

• Pulmonary Medicine
• Vascular Biology
• Cellular Biology

Background:

• Pulmonary fibrosis often involves pulmonary hypertension, suggesting vascular remodeling independent of fibrosis.
• Plasma growth differentiation factor 15 (GDF15) is elevated in fibrotic lung diseases and linked to right heart pressures, hinting at endothelial dysfunction.

Purpose of the Study:

• To investigate the role of endothelial GDF15 in the pathogenesis of lung fibrosis.
• To determine if GDF15 influences vascular permeability and cellular signaling in the lungs.

Main Methods:

• Generated endothelial cell-specific Gdf15 knockout mice.
• Administered bleomycin to induce lung injury and fibrosis.
• Performed RNA sequencing on human pulmonary microvascular endothelial cells.
• Conducted functional studies on GDF15 knockdown cells.

Main Results:

• Endothelial cell-specific Gdf15 knockout mice were protected from bleomycin-induced lung injury and fibrosis, maintaining lung function.
• GDF15 deficiency altered expression of barrier-regulatory genes in endothelial cells.
• GDF15 knockdown reduced thrombin-induced endothelial barrier disruption by modulating cytosolic Ca2+ responses.

Conclusions:

• Endothelial GDF15 is implicated as a key factor in modifying vascular permeability and Ca2+ signaling.
• Endothelial GDF15 contributes to the development of lung injury and fibrosis.
• Targeting endothelial GDF15 may offer a therapeutic strategy for fibrotic lung diseases.