Angiogenic role of lung pericytes in experimental viral lung injury

Abstract

Lung pericytes are perivascular stromal cells that surround microvascular endothelial cells. While their roles in fibrogenesis have been explored, their angiogenic functions in experimental lung injury and repair have not been characterized. RNAseq analysis of primary lung pericytes activated ex vivoreveals upregulation of novel angiogenic pathways. One gene of interest we identified is angiopoietin‐L4 (Angptl4). Stromal cells, particularly pericytes, are the primary sources of angiopoietin‐L4 in the lung. ANGPTL4 has been shown to regulate angiogenesis in cancer biology and retinal diseases. We have shown that lung pericyte‐derived ANGPTL4 promotes network formation and monolayer permeability in endothelial cells in vitro. We hypothesize that knockdown of ANGPTL4 in vivo is protective in acute viral lung injury by promoting endothelial integrity and decreasing microvascular leak during injury and resolution. Transgenic mice with inducible genetic deletion of Angptl4 and littermate controls were inoculated with mouse‐adapted human influenza virus (A/PR/8). Mice lacking Angptl4 showed decreased measures of lung injury and protein leak during the acute and resolution phases of lung injury. Future directions include identification of ANGPTL4 signaling pathways and cellular targets in the lung, and characterization of the mechanisms by which pericyte‐derived ANGPTL4 leads to persistence of endothelial dysfunction or activation in viral lung injury.