DIRECT TRANSFER OF TRANSFORMING GROWTH-FACTOR-BETA-1 GENE INTO ARTERIES STIMULATES FIBROCELLULAR HYPERPLASIA

The arterial wall responds to thrombosis or mechanical injury through the induction of specific gene products that increase cellular prolife ration and connective tissue formation. These changes result in intima l hyperplasia that is observed in restenosis and the early phases of a therosclerosis. Transforming growth factor beta1 (TGF-beta1) is a secr eted multi-functional protein that plays an important role in embryona l development and in repair following tissue injury. However, the func tion of TGF-beta1 in vascular cell growth in vivo has not been defined . In this report, we have evaluated the role of TGF-beta1 in the patho physiology of intimal and medial hyperplasia by gene transfer of an ex pression plasmid encoding active TGF-beta1 into porcine arteries. Expr ession of TGF-beta1 in normal arteries resulted in substantial extrace llular matrix production accompanied by intimal and medial hyperplasia . Increased procollagen, collagen, and proteoglycan synthesis in the n eointima was demonstrated by immunohistochemistry relative to control transfected arteries. Expression of TGF-beta1 induced a distinctly dif ferent program of gene expression and biologic response from the plate let-derived growth factor B (PDGF B) gene: procollagen synthesis induc ed by TGF-beta1 was greater, and cellular proliferation was less promi nent. These findings show that TGF-beta1 differentially modulates extr acellular matrix production and cellular proliferation in the arterial wall in vivo and could play a reparative role in the response to arte rial injury.