Stretch Regulates Alveologenesis Via Mesenchymal Gαq/11-Mediated TGFβ2 Activation

Alveolar development requires tight spatiotemporal regulation of numerous signalling pathways that are influenced by chemical and mechanical stimuli. Pericytes, perivascular mesenchymal cells, are key lung progenitor cells that are important for many developmental processes. Transforming growth factor-{beta} (TGF{beta}) is essential for alveologenesis, and the G protein subunits Gq and G11 (Gq/11) can transmit mechanical and chemical signals to activate TGF{beta} in epithelial cells. To understand the role of mesenchymal Gq/11 in lung TGF{beta} signalling and lung development, we generated a mesenchymal Gq/G11 knockout mouse (Pdgfrb-Cre+/-;Gnaqfl/fl;Gna11-/-). Pdgfrb-Cre+/-;Gnaqfl/fl;Gna11-/- mice exhibited abnormal alveolar development, with evidence of suppressed pericyte to myofibroblast differentiation and reduced lung TGF{beta}2 deposition. Cyclical mechanical stretch-induced TGF{beta} activation required Gq/11 signalling and serine protease activity, but was independent of integrins, suggesting a role for TGF{beta}2. These data highlight a previously undescribed mechanism of cyclical stretch-induced Gq/11-dependent TGF{beta}2 signalling in mesenchymal cells, which is imperative for normal alveologenesis.