Transforming Growth Factor-β Protein and Messenger RNA Expression Is Increased in the Closing Ductus Arteriosus

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Abstract
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-β (TGF-β), 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-β(TGF-β1, TGF-β2, and TGF-β3) 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-β isoforms were similar. TGF-β 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-β in the newly forming neointima and outer muscle media; this continued to increase over the next 10 d. Increased expression of TGF-β in the inner muscle media and adventitia lagged behind that of the neointima and outer muscle media. TGF-β was not found in the luminal endothelial cells at any time. In contrast to the pattern described above, the appearance of TGF-β protein differed from that of mRNA in the vasa vasorum of the ductus wall. After delivery, there was an increase in TGF-β immunoreactivity in the smooth muscle cell layers of the vasa vasorum without any concurrent mRNA expression. The appearance of TGF-β at the time of ductus closure suggests an important role for this growth factor in the reorganization of the ductus wall after birth.