Transforming Growth Factor-beta Protein and Messenger RNA Expression is Increased in the Closing Ductus Arteriosus

In full-term newborns, permanent closure of the ductus arteriosus is associated with the formation of a neointima that is characterized by extracellular matrix deposition and smooth muscle cell migration. Transforming growth factor-beta (TGF-beta), a potent modulator of extracellular matrix deposition and smooth muscle cell migration, has been found to play a role in the remodeling associated with several forms of vascular disease. We examined the protein and mRNA expression of the three mammalian isoforms of TGF-beta (TGF-beta1, TGF-beta2, and TGF-beta3) during ductus arteriosus closure in full-term lambs. We found that the temporal changes and cellular localization of the proteins and mRNAs of all three TGF-beta isoforms were similar. TGF-beta proteins and mRNAs were present in very low levels in the late-gestation fetal ductus. Within 24 h of delivery, there was enhanced expression of TGF-beta in the newly forming neointima and outer muscle media; this continued to increase over the next 10 d. Increased expression of TGF-beta in the inner muscle media and adventitia lagged behind that of the neointima and outer muscle media. TGF-beta was not found in the luminal endothelial cells at any time. In contrast to the pattern described above, the appearance of TGF-beta protein differed from that of mRNA in the vasa vasorum of the ductus wall. After delivery, there was an increase in TGF-beta immunoreactivity in the smooth muscle cell layers of the vasa vasorum without any concurrent mRNA expression. The appearance of TGF-beta at the time of ductus closure suggests an important role for this growth factor in the reorganization of the ductus wall after birth.