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 a ssociated with the formation of a neointima that is characterized by e xtracellular matrix deposition and smooth muscle cell migration. Trans forming growth factor-beta (TGF-beta), a potent modulator of extracell ular matrix deposition and smooth muscle cell migration, has been foun d to play a role in the remodeling associated with several forms of va scular disease. We examined the protein and mRNA expression of the thr ee mammalian isoforms of TGF-beta (TGF-beta(1), TGF-beta(2) and TGF-be ta(3)) during ductus arteriosus closure in full-term lambs. We found t hat 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 conti nued to increase over the next 10 d. Increased expression of TGF-beta in the inner muscle media and adventitia lagged behind that of the neo intima and outer muscle media. TGF-beta was not found in the luminal e ndothelial cells at any time. In contrast to the pattern described abo ve, the appearance of TGF-beta protein differed from that of mRNA in t he vasa vasorum of the ductus wall. After delivery, there was an incre ase in TGF-beta immunoreactivity in the smooth muscle cell layers of t he 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.