|NCI Researchers Identify Molecular Regulator
for Blood Flow in Mice
Researchers at the National Cancer Institute (NCI), part of the
National Institutes of Health (NIH), and Ohio State University,
have identified a cellular protein that acts as a regulator for
blood flow by blocking blood vessel relaxation induced by nitric
oxide (NO). This mouse study appears in the November 2, 2006, online
issue of Blood*.
“NO is a well-studied signaling molecule already known for its
important role in erectile dysfunction and heart disease,” said
NCI Director John Niederhuber, M.D. “This finding could have implications
for anti-angiogenesis therapies aimed at regulating blood flow
into tumors and improving healing after surgery.”
NO is a biologically active gas produced by many different cell
types, including the innermost cell layer lining of blood vessels.
As NO gas quickly spreads to the underlying smooth muscle cells
and halts contraction, blood vessels enlarge and blood flow increases.
In this way, NO regulates blood pressure and the distribution of
blood throughout the body. By increasing blood flow to tissues,
NO acts to offset tissue ischemia — the restriction of the
blood supply to tissues and organs. Tissue ischemia is a major
cause of tissue damage that is associated with cardiovascular disease
One protein involved in the NO-signaling pathway is called
TSP1, or thrombospondin-1. It is a multifunctional protein found
on the surface of many cell types. One identified function for
TSP1 is restriction of tumor growth by reducing the formation of
new blood vessels. TSP1 accomplishes this by counteracting the
blood vessel growth-stimulating effect of low concentrations
of NO. The development of new blood vessels, a process known as
angiogenesis, is essential for providing tumors with a fresh supply
of oxygen and nutrients. Widespread loss of TSP1 has been observed
in some types of cancer.
“The human body must carefully balance cell signaling pathways.
It is important for NO to encourage a limited amount of angiogenesis
for wound healing, but this molecular messenger must be regulated,
by TSP1 and possibly other proteins, in order to prevent uncontrolled
angiogenesis seen in tumor development and other diseases,” explained
David Roberts, Ph.D., head of the Biochemical Pathology Section
at NCI and senior author of the study.
The researchers, led by Roberts and Jeff Isenberg, M.D., NCI,
examined the control of blood vessel relaxation in mice by manipulating
cellular production of TSP1. Under laboratory conditions, treatment
with NO relaxes blood vessel muscle cells by controlling organization
of myosin and actin, proteins that work together to contract muscle
cells in vessel walls. Consistent with this finding, the addition
of NO resulted in blood vessel dilation and modestly increased
oxygen flow into the leg muscles of genetically normal mice. When
the same treatment was applied to mice engineered to lack TSP1,
dilation and blood flow increased dramatically, since these mice
did not have a functional molecule to counter the effects of NO.
Extending this work to an injury that deprives skin tissue of
blood flow and results in substantial tissue death, the researchers
found that mice without TSP1 also showed enhanced tissue survival
as compared to normal mice. This finding was attributed to increased
angiogenesis and recovery of oxygen levels, important factors in
“If you remove TSP1, you remove the natural brake on NO’s ability
to dilate blood vessels. This paradigm may play a significant role
in cancer but can also lead to improved outcomes for patients undergoing
surgery for a variety of ailments,” Isenberg concluded.
*Isenberg JS, Hyodo F, Matsumoto KI,
Romeo MJ, Abu-Asab M, Tsokos M, Kuppusamy P, Wink DA, Krishna MC,
Roberts DD. Thrombospondin-1 limits ischemic tissue survival by
inhibiting nitric oxide-mediated vascular smooth muscle relaxation.
Online November 2, 2006. Blood.
For more information on Dr. Roberts’ research, go to http://ccr.cancer.gov/staff/staff.asp?profileid=5850.
For more information about cancer, please visit the NCI Web site
at http://www.cancer.gov, or
call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237)
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