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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

Date

07/12/2013

Pubmed ID

23841513

DOI

10.1165/rcmb.2013-0147OC

Scopus ID

2-s2.0-84890045883   33 Citations

Abstract

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

Authors

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




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

Animals
Animals, Newborn
Biomechanical Phenomena
Bronchopulmonary Dysplasia
Disease Models, Animal
Elasticity
Endothelial Cells
Extracellular Matrix
Gene Expression
Hyperoxia
Low Density Lipoprotein Receptor-Related Protein-5
Lung
Lung Injury
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein-Lysine 6-Oxidase
RNA, Messenger
Receptor, TIE-2
Signal Transduction
jenkins-FCD Prod-410 e9586552fe7f53c71f7923aa6e27aeabbd3c2473