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 proliferation and connective tissue formation. These changes result in intimal hyperplasia that is observed in restenosis and the early phases of atherosclerosis. Transforming growth factor beta 1 (TGF-beta 1) is a secreted multi-functional protein that plays an important role in embryonal development and in repair following tissue injury. However, the function of TGF-beta 1 in vascular cell growth in vivo has not been defined. In this report, we have evaluated the role of TGF-beta 1 in the pathophysiology of intimal and medial hyperplasia by gene transfer of an expression plasmid encoding active TGF-beta 1 into porcine arteries. Expression of TGF-beta 1 in normal arteries resulted in substantial extracellular matrix production accompanied by intimal and medial hyperplasia. Increased procollagen, collagen, and proteoglycan synthesis in the neointima was demonstrated by immunohistochemistry relative to control transfected arteries. Expression of TGF-beta 1 induced a distinctly different program of gene expression and biologic response from the platelet-derived growth factor B (PDGF B) gene: procollagen synthesis induced by TGF-beta 1 was greater, and cellular proliferation was less prominent. These findings show that TGF-beta 1 differentially modulates extracellular matrix production and cellular proliferation in the arterial wall in vivo and could play a reparative role in the response to arterial injury.
Nabel
E G
EG
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0688.
Shum
L
L
Pompili
V J
VJ
Yang
Z Y
ZY
San
H
H
Shu
H B
HB
Liptay
S
S
Gold
L
L
Gordon
D
D
Derynck
R
R
D000818:Animals; D001158:Arteries / Q000378:metabolism / Q000473:pathology*; D001161:Arteriosclerosis / Q000473:pathology*; D001483:Base Sequence; D003094:Collagen / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006965:Hyperplasia; D008969:Molecular Sequence Data; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011347:Procollagen / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000235:genetics; D013552:Swine; D016212:Transforming Growth Factor beta / Q000502:physiology*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology
D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D010982:Platelet-Derived Growth Factor; D011347:Procollagen; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003094:Collagen