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

Pulmonary artery smooth muscle cell behaviour, including proliferation, apoptosis, and matrix production, is controlled by transforming growth factor (TGF)-β, acting via two type I (Acvrl1 and Tgbfr1) and two type III [endoglin (Eng) and betaglycan (Tgfbr3)] TGF-β receptors. Knockdown of TGFBR3 by siRNA in primary human pulmonary artery smooth muscle cells (PASMC) increased PASMC proliferation (3-fold; assessed by BrdU incorporation) in vitro , in a TGF-β-independent manner. However, apoptosis rates of the PASMC were not affected by siRNA knockdown of TGFBR3. The siRNA knockdown of other TGF-β receptors, ACVRL1, TGFBR1, TGFBR2 and ENG, did not impact TGF-β-independent proliferation or apoptosis of PASMC. These data point to a novel, TGF-β-independent role for TGFBR3 in regulating PASMC growth. This idea assumes importance considering that we have also observed perturbed expression of TGFBR3 in the lungs of neonatal mice with hyperoxia (85% O 2 )-induced lung injury, which results in bronchopulmonary dysplasia (BPD). The mRNA levels (assessed by quantitative real-time RT-PCR) for tgfbr3 were downregulated (4.4-fold, p=0.003), while TGFBR3 protein levels were downregulated by 70%. Laser capture 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.