Chorioamnionitis stimulates angiogenesis in saccular stage fetal lungs via CC chemokines.

Miller JD, Benjamin JT, Kelly DR, Frank DB, Prince LS
Am J Physiol Lung Cell Mol Physiol. 2010 298 (5): L637-45

PMID: 20172951 · PMCID: PMC2867403 · DOI:10.1152/ajplung.00414.2009

The fetal lung vasculature forms in tandem with developing airways. Whereas saccular airway morphogenesis is arrested in bronchopulmonary dysplasia (BPD), the potential vascular phenotype in BPD at this stage of development is less well-understood. As inflammation increases the risk of BPD and induces arrest of saccular airway morphogenesis, we tested the effects of Escherichia coli LPS on fetal mouse lung vascular development. Injecting LPS into the amniotic fluid of Tie2-lacZ endothelial reporter mice at embryonic day 15 stimulated angiogenesis in the saccular stage fetal lung mesenchyme. LPS also increased the number of endothelial cells in saccular stage fetal mouse lung explants. Inflammation appeared to directly promote vascular development, as LPS stimulated pulmonary microvascular endothelial cell angiogenesis, cell migration, and proliferation in vitro. Whereas LPS did not increase expression of VEGF, angiopoietin-1 (Ang-1), Tie2, fetal liver kinase-1 (Flk-1), fms-like tyrosine kinase-1 (Flt-1), PDGFA, PDGFB, heparin-binding EGF-like growth factor (HB-EGF), or connective tissue growth factor (CTGF), LPS did stimulate the production of the angiogenic CC chemokines macrophage inflammatory protein-1α (MIP-1α) and monocyte chemoattractant protein-1 (MCP-1). Both MIP-1α and MCP-1 increased angiogenesis in fetal mouse lung explants. In addition, inhibitory antibodies against MIP-1α and MCP-1 blocked the effects of LPS on fetal lung vascular development, suggesting these chemokines are downstream mediators of LPS-induced angiogenesis. We speculate that an inflammation-mediated surge in angiogenesis could lead to formation of aberrant alveolar capillaries in the lungs of patients developing BPD.

MeSH Terms (21)

Animals Bronchopulmonary Dysplasia Case-Control Studies Chemokine CCL2 Chemokine CCL3 Chemokines, CC Chorioamnionitis Disease Models, Animal Endothelial Cells Female Humans Immunity, Innate Infant Infant, Newborn Lipopolysaccharides Lung Mice Mice, Inbred BALB C Mice, Transgenic Neovascularization, Physiologic Pregnancy

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