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Built-In "Failsafe" Device Blocks Abnormal Growth Of New Blood Vessels

Date:
April 15, 2002
Source:
Northwestern University
Summary:
Some inhibitors of angiogenesis prevent new blood vessel growth by triggering a built-in "failsafe" device in vessel-forming endothelial cells that marks them for apoptosis, or programmed cell death, according to a study from The Feinberg School of Medicine at Northwestern University and Washington University at St. Louis.

CHICAGO --- Some inhibitors of angiogenesis prevent new blood vessel growth by triggering a built-in "failsafe" device in vessel-forming endothelial cells that marks them for apoptosis, or programmed cell death, according to a study from The Feinberg School of Medicine at Northwestern University and Washington University at St. Louis.

By identifying the molecular mechanisms that control this failsafe device, it may be possible to design new anti-angiogenic drugs or to improve already existing drugs to prevent abnormal blood vessel growth, says Olga Volpert, assistant professor of urology at the Feinberg School and lead author the study, which appeared in the April issue of the journal Nature Medicine.

Angiogenesis, or aberrant growth of new blood vessels, enables cancerous tumors to spread through the body and also causes diabetic retinopathy and macular degeneration, the leading causes of blindness in the Western world.

Research has shown that new blood vessel growth relies on an exquisite balance of proteins that either induce or inhibit new growth of the endothelial cells that form the walls of new blood vessels. Identifying the components that influence this balance thus has major scientific relevance for understanding angiogenesis-dependent diseases and for developing therapies to prevent neovascularization.

When certain natural inhibitors are administered as drugs against angiogenesis-dependent diseases like cancer and diabetic retinopathy, they selectively destroy only newly formed vessels, not preexisting ones -- for reasons that were unclear until now.

In the study, endothelial cells activated by an inducer expressed a cell surface protein receptor called Fas, which made the cells sensitive to the inhibitors in their environment. The inhibitors, thrombospondin-1 (TSP1) or pigment epithelial-derived factor (PEDF), activated its ligand, another cell surface protein called FasL -- which fits into the Fas receptor like a key in a lock -- initiating a molecular cascade in the cell that resulted in cell death.

These results indicate that the angiogenesis-inhibiting activity of TSP1 and PEDF was dependent on the dual induction of Fas and FasL as well as on the resulting apoptosis. It has been known for some time that Fas/FasL interactions target immune cells for destruction in immune-privileged and diseased tissues when large populations of cells are to be eliminated. The results of the current study show that these interactions also affect the fate of vascular tissues where new vessels are subject for destruction by inhibitors of angiogenesis.

The researchers also showed that TSP1 and PEDF reduced the expression of the inducer-stimulated molecule that blocks cell death. This unexpected cooperation between pro- and anti-angiogenic factors may have major implications on the therapeutic use of these two inhibitors. Fas and its ligand may serve as new targets to design anti-angiogenic drugs or to improve already existing drugs.

"The data provide an unexpected explanation for the specificity of inhibitors for activated, remodeling endothelium, thus clarifying why they can be used so effectively without side effects," Volpert said. "The data also offer new means to enhance the efficacy of these inhibitors and predict synergies between various inhibitors and between inhibitors and conventional therapies."

Co-authors from the Feinberg School were Noel P. Bouck, emeritus emeritus of microbiology-immunology, Tetiana Zaichuk, Wei Zhou, Frank Reiher and Mohammed Amin. Bouck, Zaichuk, Zhou and Reiher are researchers at The Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Washington University co-authors were Thomas A. Ferguson and Patrick Stewart, department of ophthalmology and visual sciences.


Story Source:

The above story is based on materials provided by Northwestern University. Note: Materials may be edited for content and length.


Cite This Page:

Northwestern University. "Built-In "Failsafe" Device Blocks Abnormal Growth Of New Blood Vessels." ScienceDaily. ScienceDaily, 15 April 2002. <www.sciencedaily.com/releases/2002/04/020412074814.htm>.
Northwestern University. (2002, April 15). Built-In "Failsafe" Device Blocks Abnormal Growth Of New Blood Vessels. ScienceDaily. Retrieved August 20, 2014 from www.sciencedaily.com/releases/2002/04/020412074814.htm
Northwestern University. "Built-In "Failsafe" Device Blocks Abnormal Growth Of New Blood Vessels." ScienceDaily. www.sciencedaily.com/releases/2002/04/020412074814.htm (accessed August 20, 2014).

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