Vascular Endothelial Growth Factor-D Improves Lung Vascular Integrity During Acute Lung Injury

Area of Science:

• Pulmonary vascular biology
• Cell signaling
• Molecular medicine

Background:

• Pulmonary vascular integrity is crucial for lung health, yet the specific cell-cell signals maintaining microvascular stability are poorly understood.
• Paracrine signaling in the lung regulates vascular homeostasis, but local crosstalk maintaining stability in adult lungs remains unexplored.

Purpose of the Study:

• To identify local cell-cell crosstalk signals regulating pulmonary microvascular stability.
• To investigate the role of vascular endothelial growth factor-D (VEGF-D) in maintaining lung endothelial barrier function.

Main Methods:

• Single-cell RNA-sequencing to profile ligand-receptor interactions in the lung microvascular niche.
• Computational analysis to identify key signaling pathways and factors.
• In vitro experiments assessing VEGF-D's effect on endothelial barrier function.
• In vivo studies using mouse models of acute lung injury.

Main Results:

• Single-cell RNA-sequencing identified mesenchymal cells, particularly alveolar fibroblasts, as key interactors with microvascular endothelial cells, primarily via pathways maintaining vascular integrity.
• Vascular endothelial growth factor-D (VEGF-D) significantly enhanced endothelial barrier function and protected against inflammatory challenges.
• VEGF-D's protective effects were mediated through vascular endothelial growth factor receptor 2 (VEGFR2) signaling, as confirmed by knockdown and blockade studies.
• In vivo, VEGF-D administration reduced vascular permeability, immune cell infiltration, and pro-inflammatory markers in acute lung injury models, an effect dependent on VEGFR2 in endothelial cells.

Conclusions:

• Vascular endothelial growth factor-D (VEGF-D) plays an unexpected protective role in promoting lung endothelial barrier integrity.
• Paracrine signaling from the alveolar fibroblast niche critically contributes to lung capillary homeostasis.
• VEGF-D represents a potential therapeutic target for lung injury and diseases involving vascular barrier dysfunction.