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

BACKGROUND: Disorders in pulmonary vascular integrity are a prominent feature in many lung diseases. Paracrine signaling is highly enriched in the lung and plays a crucial role in regulating vascular homeostasis. However, the specific local cell-cell crosstalk signals that maintain pulmonary microvascular stability in adult animals and humans remain largely unexplored. METHODS: In this study, we used single-cell RNA-sequencing-based computational pipelines to systematically profile ligand-receptor interactions within the lung microvascular niche and identified VEGF-D (vascular endothelial growth factor-D) as a key local factor with previously unrecognized barrier-protective properties in models of acute lung injury. RESULTS: (VEGFR2 inducible endothelial cells knockout) mice, confirming that VEGF-D mediates its effects via VEGFR2-dependent signaling. CONCLUSIONS: This study demonstrates an unexpected protective role for VEGF-D in promoting lung endothelial barrier integrity and suggests that paracrine signaling from the alveolar fibroblast niche contributes critically to lung capillary homeostasis.