Scientists at Schepens Eye Research Institute, an affiliate of Harvard Medical School, are the first to discover a switch inside blood vessel cells that controls angiogenesis (new blood vessel growth). The switch, they learned, is turned on and off by the balance between two enzymes (known as PI3K and PLCg) that compete for the use of the same lipid membrane to fulfill opposite missions, growth and regression, respectively. This finding could lead to new, more targeted drugs for diseases such as cancer, diabetic retinopathy and macular degeneration. The study, titled "Regulating angiogenesis at the level of PtdIns-4,5P2," is published in the current issue of The EMBO Journal (May 17).
"This is a significant discovery that holds great promise for future treatments," says principal investigator and senior Schepens scientist, Dr. Andrius Kazlauskas, who adds that scientists have long suspected an "intracellular" switching process, but until now have known very little about it. "Current drugs focus on suppressing angiogenesis by inhibiting a mechanism outside the vessel cells, which involves the action of growth factors such as VEGF or vascular endothelial growth factor. While effective in preventing vessel growth, these drugs have little impact on existing, stable vessels," he says. "Our discovery may help design drugs that could dismantle existing vessels by targeting this switch inside the vessel cells."
Angiogenesis is an important natural process that can be both good and bad for the body. It restores blood flow after injury, prepares a woman's body for pregnancy and increases circulation in a damaged heart. But, it can also nourish cancer tumors and damage delicate retinal tissues when uncontrolled.
The angiogenic process is triggered by what the body perceives as a need for additional blood flow. In the case of disease, it is a mistaken need. In response, the body sends growth factors (such as VEGF) to blood vessels in the "needy area" to bind to receptors on the surface of the endothelial cells. This binding then sets off a series of signaling activities carried out by enzymes within the cells. Two of those enzymes are PI3K and PLCg, which then search for their favorite lipid to use in their respective missions. Until the present study, scientists did not know exactly what those missions were and how they were accomplished.
Kazlauskas and his team were determined to answer those questions. To do so they created laboratory conditions that would allow them to observe the two enzymes separately as they acted on the lipid. In a series of "in vitro" or laboratory experiments that controlled the presence of each enzyme, they began to understand the individual roles of those enzymes.
The research team discovered the following. When the PI3K enzyme acts on the lipid, it converts it (the lipid) into a modified form of itself, which then signals blood vessel cells to proliferate or grow. The team also found that when PLCg acts on the lipid, it cuts the lipid in two, thus preventing PI3K from using that very same lipid to promote vessel growth. Instead, they learned, the resulting two halves of the lipid trigger a series of signaling activities that caused vessels to regress and disappear.
The team concluded that it was the competitive relationship between these two enzymes for the lipid that was at least part of the intracellular switch for which they and other scientists have been searching. They also concluded that blood vessel growth or regression was dependent on the relative activity of the two enzymes and on the amount of the lipid within the endothelial cells.
"Understanding this process opens a whole new avenue for treatment of angiogenesis-related diseases," says Kazlauskas. "For instance, drugs could be designed to decrease PI3K in cancer patients or those with proliferative diabetic retinopathy or macular degeneration, or designed to increased it in a damaged heart," he says.
Next steps for the research team include identifying the signaling events by which PLCg informs the vessels to undergo regression and the molecules that execute the regression command.
Schepens Eye Research Institute, an affiliate of Harvard Medical School, is the largest independent eye institute in the world.
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