Stretch regulates alveologenesis and homeostasis via mesenchymal Gαq/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-beta (TGF beta) is essential for alveologenesis and lung repair, and the G protein alpha subunits G(alpha q) and G(alpha 11) (G(alpha q/11)) transmit mechanical and chemical signals to activate TGF beta in epithelial cells. To understand the role of mesenchymal G(alpha q/11) in lung development, we generated constitutive (Pdgfrb-Cre+/-;Gnaqfl/fl;Gna11-/-) and inducible (Pdgfrb-Cre/ERT2(+/-); Gnaq(fl/fl); Gna11(-/-)) mesenchymal G(alpha q/11) deleted mice. Mice with constitutive G(alpha q/11) gene deletion exhibited abnormal alveolar development, with suppressed myofibroblast differentiation, altered mesenchymal cell synthetic function, and reduced lung TGF beta 2 deposition, as well as kidney abnormalities. Tamoxifen-induced mesenchymal G(alpha q/11) gene deletion in adult mice resulted in emphysema associated with reduced TGF beta 2 and elastin deposition. Cyclical mechanical stretch-induced TGF beta activation required G(alpha q/11) signalling and serine protease activity, but was independent of integrins, suggesting an isoform-specific role for TGF beta 2 in this model. These data highlight a previously undescribed mechanism of cyclical stretch-induced G(alpha q/11) dependent TGF beta 2 signalling in mesenchymal cells, which is imperative for normal alveologenesis and maintenance of lung homeostasis.