The role of the type III transforming growth factor-β receptors in the regulation of pulmonary vascular development

Disturbed pulmonary vascular development is increasingly recognised as a key player in the perturbed alveolar development associated with bronchopulmonary dysplasia (BPD). The molecular basis of the peturbed pulmonary vascular development is not understood. Our preliminary studies in mice, employing a hyperoxia-based model of BPD, have revealed dysregulated expression of components of the transforming growth factor (TGF)-β signalling machinery. In this study, we particularly address the type I and type III TGF-β receptors, in pulmonary vascular smooth muscle behaviour. These receptors include two type I (Acvrl1 and Tgbfr1) and two type III [endoglin (Eng) and betaglycan (Tgfbr3)] receptors.

Preliminary immunohistochemical studies suggested that the changes in TGF-β receptor expression were largely confined to the pulmonary vascular smooth muscle, suggesting a possible role for these receptors in the smooth muscle tissue in the development of BPD. Knockdown of TGFBR3 in PASMCs increased PASMC proliferation two-fold in vitro, in a TGF-β-independent manner (revealed by parallel trends in proliferation observed in the presence of the TGF-β pathway inhibitor SB431542). However, apoptosis of PASMCs was not affected by the knockdown of TGFBR3. Furthermore, Tgfbr3 expression is markedly perturbed in the lungs of neonatal mice with hyperoxia (85% O2)-induced lung injury, a popular animal model of BPD. The mRNA expression of tgfbr3 was downregulated (4.4-fold, respectively) while eng mRNA levels were upregulated (2.7-fold). Laser microdissection confirmed dysregulated expression of TGFBR3 in the pulmonary vasculature of the developing mouse lung.

Taken together, these data suggest a role for TGFBR3 in vascular smooth muscle cell function which could lead to a dysregulation of TGF-β signalling in the pulmonary vasculature which in turn could contribute to the impaired pulmonary vascular growth and development associated with the lung hypoplasia observed in patients with BPD.