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LRP5 regulates development of lung microvessels and alveoli through the angiopoietin-Tie2 pathway. PLoS One 2012;7(7):e41596

Date

08/01/2012

Pubmed ID

22848540

Pubmed Central ID

PMC3404972

DOI

10.1371/journal.pone.0041596

Scopus ID

2-s2.0-84864355628 (requires institutional sign-in at Scopus site)   32 Citations

Abstract

Angiogenesis is crucial for lung development. Although there has been considerable exploration, the mechanism by which lung vascular and alveolar formation is controlled is still not completely understood. Here we show that low-density lipoprotein receptor-related protein 5 (LRP5), a component of the Wnt ligand-receptor complex, regulates angiogenesis and alveolar formation in the lung by modulating expression of the angiopoietin (Ang) receptor, Tie2, in vascular endothelial cells (ECs). Vascular development in whole mouse lungs and in cultured ECs is controlled by LRP5 signaling, which is, in turn, governed by a balance between the activities of the antagonistic Tie2 ligands, Ang1 and Ang2. Under physiological conditions when Ang1 is dominant, LRP5 knockdown decreases Tie2 expression and thereby, inhibits vascular and alveolar development in the lung. Conversely, when Ang2 dominates under hyperoxia treatment in neonatal mice, high LRP5 and Tie2 expression suppress angiogenesis and lung development. These findings suggest that the LRP5-Tie2-Ang signaling axis plays a central role in control of both angiogenesis and alveolarization during postnatal lung development, and that deregulation of this signaling mechanism might lead to developmental abnormalities of the lung, such as are observed in bronchopulmonary dysplasia (BPD).

Author List

Mammoto T, Chen J, Jiang E, Jiang A, Smith LE, Ingber DE, Mammoto A

Authors

Akiko Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Tadanori Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Angiopoietin-1
Angiopoietin-2
Animals
Cell Hypoxia
Endothelial Cells
Gene Expression Regulation
Humans
Low Density Lipoprotein Receptor-Related Protein-5
Mice
Mice, Inbred C57BL
Microvessels
Pulmonary Alveoli
Receptor Protein-Tyrosine Kinases
Receptor, TIE-2
Signal Transduction