Endothelial Sash1 Is Required for Lung Maturation through Nitric Oxide Signaling

The sterile alpha motif (SAM) and SRC homology 3 (SH3) domain containing protein 1 (Sash1) acts as a scaffold in TLR4 signaling. We generated Sash1−/− mice, which die in the perinatal period due to respiratory distress. Constitutive or endothelial-restricted Sash1 loss leads to a delay in maturation...

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Published in:Cell reports (Cambridge) 2019-05, Vol.27 (6), p.1769-1780.e4
Main Authors: Coulombe, Patrick, Paliouras, Grigorios N., Clayton, Ashley, Hussainkhel, Angela, Fuller, Megan, Jovanovic, Vida, Dauphinee, Shauna, Umlandt, Patricia, Xiang, Ping, Kyle, Alistair H., Minchinton, Andrew I., Humphries, R. Keith, Hoodless, Pamela A., Parker, Jeremy D.K., Wright, Joanne L., Karsan, Aly
Format: Article
Language:English
Subjects:
alveolar type 2 cells
endothelium
lung development
nitric oxide
respiratory distress
Sash1
surfactant
TLR4
β-arrestin
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Summary:The sterile alpha motif (SAM) and SRC homology 3 (SH3) domain containing protein 1 (Sash1) acts as a scaffold in TLR4 signaling. We generated Sash1−/− mice, which die in the perinatal period due to respiratory distress. Constitutive or endothelial-restricted Sash1 loss leads to a delay in maturation of alveolar epithelial cells causing reduced surfactant-associated protein synthesis. We show that Sash1 interacts with β-arrestin 1 downstream of the TLR4 pathway to activate Akt and endothelial nitric oxide synthase (eNOS) in microvascular endothelial cells. Generation of nitric oxide downstream of Sash1 in endothelial cells affects alveolar epithelial cells in a cGMP-dependent manner, inducing maturation of alveolar type 1 and 2 cells. Thus, we identify a critical cell nonautonomous function for Sash1 in embryonic development in which endothelial Sash1 regulates alveolar epithelial cell maturation and promotes pulmonary surfactant production through nitric oxide signaling. Lung immaturity is a major cause of respiratory distress and mortality in preterm infants, and these findings identify the endothelium as a potential target for therapy. [Display omitted] •Sash1 signaling in the pulmonary endothelium triggers alveolar cell maturation•Sash1 interacts with β-arrestin1 to activate Akt-eNOS•Endothelial NO stimulates alveolar cell maturation in an sGC-cGMP-dependent manner Surfactant deficiency due to lung immaturity is a major cause of respiratory distress in premature newborns. Coulombe et al. show that endothelial SAM and SH3 domain containing protein 1 (Sash1) drives perinatal lung maturation via nitric oxide signaling to alveolar cells. Sash1 interacts with β-arrestin1 to activate Akt-eNOS and induce alveolar epithelial cell maturation and surfactant synthesis.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2019.04.039