Stretch regulates alveologenesis and homeostasis via mesenchymal G(αq/11)-mediated TGFβ2 activation

Alveolar development and repair require tight spatiotemporal regulation of numerous signalling pathways that are influenced by chemical and mechanical stimuli. Mesenchymal cells play key roles in numerous developmental processes. Transforming growth factor-β (TGFβ) is essential for alveologenesis and lung repair, and the G protein α subunits G(αq) and G(α11) (G(αq/11)) transmit mechanical and chemical signals to activate TGFβ in epithelial cells. To understand the role of mesenchymal G(αq/11) in lung development, we generated constitutive (Pdgfrb-Cre(+/−);Gnaq(fl/fl);Gna11(−/−)) and inducible (Pdgfrb-Cre/ERT2(+/−);Gnaq(fl/fl);Gna11(−/−)) mesenchymal G(αq/11) deleted mice. Mice with constitutive G(αq/11) gene deletion exhibited abnormal alveolar development, with suppressed myofibroblast differentiation, altered mesenchymal cell synthetic function, and reduced lung TGFβ2 deposition, as well as kidney abnormalities. Tamoxifen-induced mesenchymal G(αq/11) gene deletion in adult mice resulted in emphysema associated with reduced TGFβ2 and elastin deposition. Cyclical mechanical stretch-induced TGFβ activation required G(αq/11) signalling and serine protease activity, but was independent of integrins, suggesting an isoform-specific role for TGFβ2 in this model. These data highlight a previously undescribed mechanism of cyclical stretch-induced G(αq/11)-dependent TGFβ2 signalling in mesenchymal cells, which is imperative for normal alveologenesis and maintenance of lung homeostasis.