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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2461-2470.)
© 1997 American Heart Association, Inc.

Articles

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

Michael R. Ward; Alex Agrotis; Peter Kanellakis; Rodney Dilley; Garry Jennings; ; Alex Bobik

From the Cell Biology Laboratory, Baker Medical Research Institute, and Alfred Baker Medical Unit, Alfred Hospital, Prahran, Australia.

Correspondence to Dr M. Ward, Cell Biology Laboratory, Baker Medical Research Institute, Commercial Rd, Prahran, VIC 3181, Australia. E-mail mward{at}Baker.edu.au

Abstract Transforming growth factor-ß₁ (TGF-ß₁) has been implicated in neointima formation in mechanically injured vessels and in restenosis after angioplasty. To further understand the significance of TGF-ßs in neointima formation, we examined the temporal expression of three TGF-ß isoforms (-ß₁, -ß₂, and -ß₃), their receptors (ALK-2, ALK-5, and TßRII), and two putative TGF-ß responses (elevations in _v and ß₃ 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-ß₁, -ß₂, and -ß₃ during the 48 hours immediately after injury, which were localized to the vessel's media. TGF-ß₁ mRNA increased 10-fold during this time while TGF-ß₃ mRNA also increased almost 2-fold. There were also increases in mRNAs encoding the TGF-ß type I receptors ALK-5 and ALK-2, as well as the type II receptor (TßRII). 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-ß₁, TGF-ß₃, ALK-5, and TßRII immunoreactive peptide levels. Peak increases in mRNAs for integrins _v and ß₃ averaged approximately 2-fold and 2.5-fold, respectively. Perivascular administration of the tyrosine kinase inhibitor genistein at the time of vessel injury markedly (>85%) inhibited elevations in mRNAs encoding TGF-ß₁, TGF-ß₃, TßRII, and the two integrins _v and ß₃, while application of its inactive chemically similar homologue daidzein did not prevent the injury-induced elevations in mRNA levels. Since the increases in integrins _v and ß₃ mRNA could be theoretically attributed to TGF-ß actions despite being dependent on tyrosine kinase activity, we examined whether the observed elevations in integrins _v and ß₃ were due to TGF-ß₁ secretion, using cultured rat carotid artery smooth muscle cells. TGF-ß₁ neutralizing antibodies specifically inhibited elevations in integrins _v and ß₃ mRNAs due to platelet-derived growth factor-BB and fibroblast growth factor-2. We conclude that multiple components of the TGF-ß system in vessels are activated following injury and influence expression of integrin receptors important for smooth muscle cell migration. Activation of the TGF-ß system appears to be highly dependent on tyrosine kinases.

Key Words: transforming growth factor-ß • receptors • integrins _v and ß₃ • protein tyrosine kinase inhibitors • balloon catheter injury

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