Endothelial Sash1 Is Required for Lung Maturation through Nitric Oxide Signaling

• Main Authors: Patrick Coulombe, Grigorios N. Paliouras, Ashley Clayton, Angela Hussainkhel, Megan Fuller, Vida Jovanovic, Shauna Dauphinee, Patricia Umlandt, Ping Xiang, Alistair H. Kyle, Andrew I. Minchinton, R. Keith Humphries, Pamela A. Hoodless, Jeremy D.K. Parker, Joanne L. Wright, Aly Karsan
• Format: Article
• Language: English
• Published: Elsevier 2019-05-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124719305042

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. : 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. Keywords: TLR4, Sash1, surfactant, endothelium, alveolar type 2 cells, respiratory distress, lung development, β-arrestin, nitric oxide