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Transforming growth factor-β1 (TGF-β1 ) has been implicated in neointima formation in mechanically injured vessels and in restenosis after angioplasty. To further understand the significance of TGF-βs in neointima formation, we examined the temporal expression of three TGF-β isoforms (-β1 , -β2 , and -β3 ), their receptors (ALK-2, ALK-5, and TβRII), and two putative TGF-β responses (elevations in αv and β3 integrin mRNAs) in balloon catheter–injured rat carotid arteries and their dependency on tyrosine kinase activity. Using a standardized reverse transcriptase–polymerase chain reaction assay optimized to estimate mRNA levels, we observed distinct patterns of mRNA regulation for TGF-β1 , -β2 , and -β3 during the 48 hours immediately after injury, which were localized to the vessel’s media. TGF-β1 mRNA increased 10-fold during this time while TGF-β3 mRNA also increased almost 2-fold. There were also increases in mRNAs encoding the TGF-β type I receptors ALK-5 and ALK-2, as well as the type II receptor (TβRII). Eight hours after the injury, mRNA levels for ALK-2 and ALK-5 were on average 2-fold higher; mRNA encoding the type II receptor increased approximately 3-fold by 24 hours. There were also associated increases in TGF-β1 , TGF-β3 , ALK-5, and TβRII immunoreactive peptide levels. Peak increases in mRNAs for integrins αv and β3 averaged approximately 2-fold and 2.5-fold, respectively. Perivascular administration of the tyrosine kinase inhibitor genistein at the time of vessel injury markedly (&gt;85%) inhibited elevations in mRNAs encoding TGF-β1 , TGF-β3 , TβRII, and the two integrins αv and β3 , while application of its inactive chemically similar homologue daidzein did not prevent the injury-induced elevations in mRNA levels. Since the increases in integrins αv and β3 mRNA could be theoretically attributed to TGF-β actions despite being dependent on tyrosine kinase activity, we examined whether the observed elevations in integrins αv and β3 were due to TGF-β1 secretion, using cultured rat carotid artery smooth muscle cells. TGF-β1 neutralizing antibodies specifically inhibited elevations in integrins αv and β3 mRNAs due to platelet-derived growth factor-BB and fibroblast growth factor-2. We conclude that multiple components of the TGF-β system in vessels are activated following injury and influence expression of integrin receptors important for smooth muscle cell migration. Activation of the TGF-β system appears to be highly dependent on tyrosine kinases.

arteriosclerosis, thrombosis, and vascular biology

Inhibition of Protein Tyrosine Kinases Attenuates Increases in Expression of Transforming Growth Factor-β Isoforms and Their Receptors Following Arterial Injury