STANFORD, Calif., Jul 2, 2001 (BUSINESS WIRE) -- Nicotine promotes the growth
of new blood vessels and can also stimulate tumor growth and the build up of
plaque inside arteries, say researchers at Stanford University Medical Center.
The finding is the first proof that nicotine affects blood vessel formation. It
suggests that while nicotine treatment may be useful to revive tissue deprived
of blood by a stroke or heart attack, physicians should exercise caution when
considering the long-term use of nicotine as a treatment. Currently the chemical
is a useful tool in smoking-cessation programs and is being studied as a
potential therapy for Alzheimer's and Parkinson's diseases, as well as chronic
pain.
The scientists, led by John P. Cooke, M.D., Ph.D., tested levels of nicotine
similar to those that would be found in a moderate smoker puffing about 20
cigarettes each day. They emphasize, however, that it's difficult to directly
compare nicotine's effects with those caused by tobacco smoke, which contains
thousands of additional components. The results of the study are published in
the July issue of Nature Medicine.
In a series of experiments, the researchers found that nicotine could enhance
new blood vessel growth in mice whose hind limbs were artificially starved of
oxygen. They also found that lung cancer cells implanted into mice grew more
quickly when the mice consumed nicotine in their drinking water. Mice
susceptible to developing plaque in the arteries of their hearts also
experienced more rapid plaque growth when exposed to nicotine than mice who were
not exposed.
The researchers believe nicotine works by binding to a receptor on the surface
of endothelial cells that recognizes acetylcholine -- a chemical that nerve
cells use to communicate with each other. Endothelial cells line the interior of
blood vessels throughout the body. These nicotinic acetylcholine receptors were
only recently discovered outside the central nervous system and their function
is not well understood. The ability of nicotine to modulate the activity of
these receptors in the central nervous system renders it a potential therapy for
neurologic disorders.
Researchers speculate that when nicotine binds to the receptor on endothelial
cells it stimulates the cells to release a cascade of chemicals that promote the
formation of new blood vessels. The new vessels then deliver oxygen and
nutrients to the interior of tumors and plaque deposits.
The Stanford researchers were surprised to find how strongly nicotine stimulates
new blood vessel growth, a process known as angiogenesis.
"We expected to see that nicotine impairs angiogenesis because it's known that
smoking impairs endothelial function," said Chris Heeschen, the first author of
the paper and a postdoctoral fellow in cardiovascular medicine in Cooke's
laboratory. "But nicotine is not smoking."
Under some experimental conditions the magnitude of nicotine's effect was
comparable to that seen with naturally occurring proteins involved in
angiogenesis. In every case, chemicals known to inhibit other molecules
associated with angiogenesis also blocked the effect of nicotine -- confirming
that nicotine affects blood vessel formation.
The researchers began the study by testing whether nicotine could stimulate the
division of cultured endothelial cells. They found that nicotine was as
effective as vascular endothelial growth factor, or VEGF -- a naturally
occurring, well-defined protein that has long been known to enhance endothelial
cell proliferation. Cells cultured in the presence of nicotine or VEGF also
assembled themselves into whorls in the tissue culture dish -- perhaps a
preliminary step to forming new blood vessels. Chemicals that block nicotine's
binding to the receptor also blocked proliferation of the cells.
The researchers also found that nicotine enhanced the vascularization of discs
implanted under the skin of mice as well as another naturally occurring
compound, known as fibroblast growth factor. The discs cause inflammation, which
frequently stimulates new blood vessel growth.
To test the ability of nicotine to restore blood flow in oxygen-starved tissue,
the researchers tied off a main artery that supplies blood to one hind limb in
mice, and then injected nicotine daily into the affected leg. After three weeks
the nicotine-injected limbs sported a higher blood vessel density and were
receiving more blood flow than those that had been injected with a saline
solution.
Finally, the researchers tested nicotine's effect on diseases such as lung
cancer and atherosclerosis. They found after only a few days that lung cancer
cells implanted under the skin or in the lung tissue of animals who drank
nicotine-laced water grew much more quickly and were more densely packed with
blood vessels than cancers in animals who were not exposed to nicotine. Mice
bred to accumulate plaque in the linings of their arteries also suffered from
nicotine exposure. The plaque blockages grew more quickly and were thicker in
these mice than in the control animals.
The acceleration of tumor and plaque growth raises a concern about the use of
nicotine in patches or gum as an adjunct to smoking-cessation programs. However,
Cooke pointed out that "it is critical for people to stop smoking because of the
strong evidence that tobacco markedly increases your risk of heart attack,
stroke, cancer and lung disease. Therefore, the benefits of nicotine patches and
gums far outweigh the risks when the products are used as directed."
Cooke and his colleagues plan to continue their research into the effects of
nicotine on angiogenesis. They are investigating how nicotine's ability to
enhance blood flow to oxygen-starved tissue could be used therapeutically. Local
application of the small, easy-to-deliver nicotine molecule to the affected
tissue might be the key to avoiding unwanted angiogenesis, Heeschen said, as
well as reducing the amount of time an individual receives nicotine therapy.
In addition to Cooke and Heeschen, the other Stanford investigators involved in
the study were James Jang, M.D.; Michael Weis, M.D.; Anjali Pathak, M.D.;
Shuichiro Kaji; Robert Hu, M.D.; Philip Tsao, Ph.D.; and Frances Johnson, M.D.
The study was funded by the National Heart, Lung and Blood Institute, the
Tobacco Related Disease Research Program and the German Research Council.
Stanford and the authors have patented the use of nicotine for therapeutic
angiogenesis. This patent has been licensed to Endovasc, Inc. and may generate
royalties for the authors.
