From the Department of Geriatric Medicine (N.N., R.M., A.M., Y.N., S.H.,
M.A., I.K., J.H., T.O.) and the Division of Biochemistry (K.M., T.N.),
Biomedical Research Center, Osaka University Medical School, Osaka, Japan.
Correspondence to Toshio Ogihara, MD, PhD, Department of Geriatric Medicine, Osaka University Medical School, 2–2 Yamada-oka, Suita 565, Japan.
Abstract—Because
hepatocyte growth factor (HGF) is a member of the
endothelium-specific growth factors, we hypothesized
that HGF may play a role in cardiovascular disease.
Therefore we first examined the role of local HGF production in
endothelial cell (EC) growth. Addition of anti-HGF
antibody to EC resulted in a significant decrease in EC number.
Moreover, coculture of vascular smooth muscle cells (VSMC) with EC
resulted in an increase in EC number that was completely inhibited by
anti-HGF antibody, suggesting that HGF secreted from EC and VSMC
regulates EC growth in an autocrine-paracrine manner. Interestingly,
transforming growth factor (TGF)-ß significantly decreased HGF
secretion from EC, whereas interleukin 6 stimulated immunoreactive HGF
secretion. In human VSMC, TGF-ß and angiotensin II
suppressed local HGF production in a dose-dependent manner.
Interestingly, anti–TGF-ß antibody resulted in significant but not
complete inhibition of the decrease in local HGF production. To
further study the regulation of local HGF production, we used a
coculture system. Coculture of VSMC with EC resulted in a significant
decrease in local HGF secretion. The decrease in local HGF
production by coculture was significantly attenuated by
anti–TGF-ß antibody, suggesting that inhibition of local HGF
production in the coculture system was due to TGF-ß
activation. Moreover, a further decrease in local HGF
production in the coculture system by angiotensin
II was also observed. Finally, we studied the role of
angiotensin II in the regulation of the local HGF system in
vivo by using a balloon injury rat model. Of importance, local HGF
production was significantly decreased in balloon-injured
arteries compared with intact vessels, accompanied by a reduction of
HGF mRNA. An angiotensin-converting enzyme
inhibitor (cilazapril) or an angiotensin II
type 1 receptor antagonist (E-4177) significantly
stimulated local vascular HGF production associated with the
inhibition of neointimal formation after balloon injury
compared with vehicle. In contrast, hydralazine did not alter
local HGF production or neointimal formation
despite decreasing blood pressure to a similar level as that in rats
treated with cilazapril or E-4177. Overall, local HGF secretion from
vascular cells was negatively regulated by TGF-ß and
angiotensin II. The present study also demonstrated
that blockade of angiotensin II significantly inhibited
neointimal formation, accompanied by a significant increase
in local vascular HGF production in vivo in the balloon injury
model. Given the strong mitogenic activity of HGF on
endothelial cells, increased local HGF
production by blockade of angiotensin II may
enhance reendothelialization after balloon injury.
Downregulation of the local vascular HGF system by TGF-ß and vascular
angiotensin may play an important role in the pathogenesis
of cardiovascular diseases.
© 1998 American Heart Association, Inc.
Scientific Contributions
Negative Regulation of Local Hepatocyte Growth Factor Expression by Angiotensin II and Transforming Growth Factor-ß in Blood Vessels
Potential Role of HGF in Cardiovascular Disease
Key Words: endothelium • muscle, smooth, vascular • autocrine-paracrine • restenosis • remodeling
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