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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online June 8, 2001 as doi:10.1096/fj.01-0028fje. |
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Laboratory of Angiogenesis Research, Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden
3Correspondence: Laboratory of Angiogenesis Research, Microbiology and Tumor Biology Center (MTC), Nobelvägen 16, Karolinska Institute, S-171 77 Stockholm, Sweden. E-mail: yihai.cao{at}mtc.ki.se
SPECIFIC AIMS
We investigate whether resveratrol, a natural polyphenol compound found in various plants including grapes and their related products, could inhibit endothelial cell growth and act as an oral angiogenesis inhibitor. The antiangiogenic property of resveratrol was examined in several in vivo models including the mouse corneal model, the chick chorioallantoic membrane assay, a wound-healing model, and a tumor model.
PRINCIPAL FINDINGS
1. Inhibition of endothelial cell growth and MAP kinase
To determine whether resveratrol, a phytoalexin and a polyphenol
compound, could inhibit endothelial cell growth, we assayed resveratrol
on bovine capillary endothelial (BCE) cells stimulated with fibroblast
growth factor 2 (FGF-2). Resveratrol inhibited capillary endothelial
cell growth in a dose-dependent manner. MAP kinase is a critical
component in signaling pathways of endothelial cell proliferation. We
examined the effect of resveratrol on FGF-2-induced activation of MAP
kinases in BCE cells. It significantly inhibited FGF-2-induced
phosphorylation of MAPKp44 and
MAPKp42 in BCE cells. Our data demonstrate that
resveratrol inhibits the phosphorylation of MAP kinases induced by
growth factors.
To study whether resveratrol could inhibit FGF-2 and VEGF receptor-mediated endothelial cell proliferation and migration, porcine aortic endothelial cell lines that stably express FGFR-1 or VEGFR-2 (PAE/FGFR-1 and PAE/VEGFR-2) receptor were used. Resveratrol inhibited, in a dose-dependent manner, the FGF-2- and VEGF-induced proliferation and migration of PAE/FGFR-1 and PAE/VEGFR-2 cells, respectively. These data demonstrate that resveratrol inhibits both FGF-2 and VEGF receptor-mediated endothelial cell growth and chemotaxis.
2. Inhibition of angiogenesis in developing embryos
To study the antiangiogenic activity of resveratrol in vivo, we
then examined its inhibitory effect on angiogenesis in the chick
chorioallantoic membrane (CAM) assay. In a concentration range of
1–100 µg per disc, resveratrol was able to induce avascular zones in
the developing CAMs, and the observed inhibition was dose-dependent. No
avascular zones were detected in the control CAMs implanted with PBS.
3. Inhibition of FGF- and VEGF-induced angiogenesis
To further investigate whether resveratrol could suppress
angiogenesis in mammals, we prepared a drinking solution for mice that
contained a low amount of resveratrol equivalent to the amount found in
approximate 3 glasses of red wine per day for humans, and assayed its
inhibitory effect in the corneal neovascularization model. This
resveratrol-containing fluid significantly inhibited corneal
neovascularization induced by VEGF (Fig. 1C
) and FGF-2 (Fig. 1D
) vs. control groups
that drank water alone (Fig. 1A
, B
). The areas of corneal
neovascularization were significantly inhibited in the
resveratrol-drinking group (Fig. 1G
, H
). In
addition, the vessel density was significantly reduced in the
resveratrol-drinking group (Fig. 1F
, I
) compared with
the control group (Fig. 1E
, I
) in the FGF-2-implanted
corneas.
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4. Suppression of tumor growth and wound healing
Tumor growth is angiogenesis dependent. The antiangiogenic effect
of resveratrol led us to investigate whether this compound was able to
inhibit the growth of a murine fibrosarcoma in mice. Oral
administration of resveratrol at the concentration of 5.7 µg/ml,
which corresponds to 25 µM, significantly inhibited the growth of
T241 fibrosarcoma in mice (T/C=0.47) (Fig. 2A
).
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In addition to tumor growth, wound healing also requires angiogenesis.
We then tested the anti-wound-healing effect of resveratrol in a mouse
skin model. Oral administration of resveratrol of the same dose as in
the tumor experiment significantly delayed wound healing in mice as
measured by the sizes of wounds and percentage of animals with healed
wounds (Fig. 2B
, C
, D
). Sizes of the wounds measured in the
resveratrol-drinking group were significantly larger from day 2 and
onward. These findings indicate that resveratrol is a novel oral
angiogenesis inhibitor.
CONCLUSIONS AND SIGNIFICANCE
Our results for the first time demonstrate that resveratrol acts
as an angiogenesis inhibitor when administrated orally. Consequently,
it inhibits angiogenesis-dependent physiological and pathological
processes including wound healing and tumor growth. Its antiangiogenic
mechanisms involve direct inhibition of capillary endothelial cell
growth via suppression of the phosphorylation of the mitogen-activated
kinase. This pathway appears to be common for two of the key factors,
i.e., FGF-2- and VEGF-induced angiogenesis, because resveratrol
inhibits both FGF receptor- and VEGF receptor-mediated endothelial cell
responses (Fig. 3
).
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The growth of primary tumors and metastases depends on the degree of tumor neovascularization. Our present study provides compelling evidence that suppression of angiogenesis could be at least one of the mechanisms of the antitumor effect of resveratrol. Consumption of resveratrol could be beneficial in the prevention of angiogenesis-dependent diseases. However, we should emphasize that the antiangiogenic effect of resveratrol could be harmful in situations such as wound healing.
Recent studies suggest that antiangiogenic therapy has to be delivered for long periods in order to arrest a tumor at its dormant stage. In clinical settings, most angiogenesis inhibitors have to be delivered to cancer patients by systemic injections for several years. Thus, there would be great advantages if oral angiogenesis inhibitors were available. As a small molecule and an oral angiogenesis inhibitor found in natural food products, resveratrol could well fulfill the criteria of long-term antiangiogenic therapy without injections. However, long-term consumption of resveratrol-enriched wine products may cause adverse health effects due to the alcohol content. Thus, there should be a caution not to encourage people to consume large amounts of wine rather than a moderate amount of red wine (2–3 glasses/day). Other food products and nonalcoholic beverages could be considered as alternative resveratrol sources.
Taken together with our other recent finding that epigallocatechin-3-gallate in green tea is an angiogenesis inhibitor, consumption of various plant products containing polyphenol-based compounds and adequate amounts of red wine may become beneficial in the prevention of cancer. Paradoxically, they might delay physiological processes in which angiogenesis is required.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.01-0028fje ; to cite this
article, use FASEB J. (June 8, 2001) 10.1096/fj.01-0028fje 
2 These authors contributed equally to this work.
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5 mm in diameter)
were created on female 6- to 7-wk-old C57Bl6/J mice by surgery.
Resveratrol was added to the drinking fluid and diameters of wounds
were measured daily. D) Data presented as mean
determinants (±SE) of wounds of six mice in each
group.