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

Abstract

SummaryAlveolar 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-β (TGFβ) is essential for alveologenesis, and the G protein α subunits Gαq and Gα11 (Gαq/11) can transmit mechanical and chemical signals to activate TGFβ in epithelial cells. To understand the role of mesenchymal Gαq/11 in lung TGFβ signalling and lung development, we generated a mesenchymal Gαq/Gα11 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 TGFβ2 deposition. Cyclical mechanical stretch-induced TGFβ activation required Gαq/11 signalling and serine protease activity, but was independent of integrins, suggesting a role for TGFβ2. These data highlight a previously undescribed mechanism of cyclical stretch-induced Gαq/11-dependent TGFβ2 signalling in mesenchymal cells, which is imperative for normal alveologenesis.