Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Extracellular matrix structure and tissue stiffness control postnatal lung development through the lipoprotein receptor-related protein 5/Tie2 signaling system. Am J Respir Cell Mol Biol 2013 Dec;49(6):1009-18



Pubmed ID




Scopus ID

2-s2.0-84890045883   51 Citations


Physical properties of the tissues and remodeling of extracellular matrix (ECM) play an important role in organ development. Recently, we have reported that low-density lipoprotein receptor-related protein (LRP) 5/Tie2 signaling controls postnatal lung development by modulating angiogenesis. Here we show that tissue stiffness modulated by the ECM cross-linking enzyme, lysyl oxidase (LOX), regulates postnatal lung development through LRP5-Tie2 signaling. The expression of LRP5 and Tie2 is up-regulated twofold in lung microvascular endothelial cells when cultured on stiff matrix compared to those cultured on soft matrix in vitro. LOX inhibitor, β-aminopropionitrile, disrupts lung ECM (collagen I, III, and VI, and elastin) structures, softens neonatal mouse lung tissue by 20%, and down-regulates the expression of LRP5 and Tie2 by 20 and 60%, respectively, which leads to the inhibition of postnatal lung development (30% increase in mean linear intercept, 1.5-fold increase in air space area). Importantly, hyperoxia treatment (Postnatal Days 1-10) disrupts ECM structure and stiffens mouse lung tissue by up-regulating LOX activity, thereby increasing LRP5 and Tie2 expression and deregulating alveolar morphogenesis in neonatal mice, which is attenuated by inhibiting LOX activity. These findings suggest that appropriate physical properties of lung tissue are necessary for physiological postnatal lung development, and deregulation of this mechanism contributes to postnatal lung developmental disorders, such as bronchopulmonary dysplasia.

Author List

Mammoto T, Jiang E, Jiang A, Mammoto A


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

Animals, Newborn
Biomechanical Phenomena
Bronchopulmonary Dysplasia
Disease Models, Animal
Endothelial Cells
Extracellular Matrix
Gene Expression
Low Density Lipoprotein Receptor-Related Protein-5
Lung Injury
Mice, Inbred C57BL
Mice, Knockout
Protein-Lysine 6-Oxidase
RNA, Messenger
Receptor, TIE-2
Signal Transduction