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Thursday, November 2, 2006
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 and diabetes.
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 wound repair.
“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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