Cells respond to deletion of CAV1 by increasing synthesis of extracellular matrix

Abstract

A range of cellular functions have been attributed to caveolae, flask-like invaginations of the plasma membrane. Here, we have used RNA-seq to achieve quantitative transcriptional profiling of primary embryonic fibroblasts from caveolin 1 knockout mice (CAV1-/- MEFs), and thereby to gain hypothesis-free insight into how these cells respond to the absence of caveolae. Components of the extracellular matrix were decisively over-represented within the set of genes displaying altered expression in CAV1-/- MEFs when compared to congenic wild-type controls. This was confirmed biochemically and by imaging for selected examples. Up-regulation of components of the extracellular matrix was also observed in a second cell line, NIH-3T3 cells genome edited to delete CAV1. Up-regulation of components of the extracellular matrix was detected in vivo by assessing collagen deposition and compliance of CAV1-/- lungs. We discuss the implications of these findings in terms of the cellular function of caveolae.

Mechanical stretch activates piezo1 in caveolae of alveolar type I cells to trigger ATP release and paracrine stimulation of surfactant secretion from alveolar type II cells

“…24,28 In part, this has been attributed to increased ECM production by mesenchymal cells, inflammation, and cell proliferation. 29 However, our data suggest another important role of caveolin-1 and caveolae for maintaining alveolar and lung homeostasis via regulating surfactant secretion from ATII cells. Impaired surfactant secretion results in surfactant dysfunction which fails to stabilize alveoli at low lung volumes during ventilation.…”

“…Hence, the mechanical properties of the distal lung are severely 24,28 . In part, this has been attributed to increased ECM production by mesenchymal cells, inflammation, and cell proliferation 29 . However, our data suggest another important role of caveolin‐1 and caveolae for maintaining alveolar and lung homeostasis via regulating surfactant secretion from ATII cells.…”

“…Extracellular ATP then amplifies Ca 2+ -signaling in ATI cells and stimulates Ca 2+ signals and LB exocytosis in neighboring ATII cells via activation of P2Y 2 receptors wall and resemble a fibrotic phenotype with reduced lung compliance. 29 Hence, the mechanical properties of the distal lung are severely. 24,28 In part, this has been attributed to increased ECM production by mesenchymal cells, inflammation, and cell proliferation.…”

“…Lungs from caveolin‐1 deficient mice have constricted alveolar spaces, associated with a thickening of the alveolar wall and resemble a fibrotic phenotype with reduced lung compliance 29 . Hence, the mechanical properties of the distal lung are severely 24,28 .…”

“…Indeed, lungs from cav1 −/− mice have constricted alveolar spaces, associated with a thickening of the alveolar wall and resemble a fibrotic phenotype. 24,28,29 Interestingly, caveolae are absent from ATII cells. 30 Next to their role in mechanosensation and mechanoprotection, caveolae have also been described to function in endocytosis and transcytosis, in maintaining membrane lipid composition, as well as acting as signaling platforms.…”