Study finds blocking angiogenesis signaling from inside cell may lead to serious healt...(ay occur when patients remain on the dru...)

In the three-year study, Iruela-Arispe created mice that were missing VEGF in the endothelial cells, the cells that line the inside of blood vessels and form an interface between circulating blood and the vessel wall. Endothelial cells line the circulatory system from the heart to the smallest capillary and reduce friction of the flow of blood. Iruela-Arispe and her team didnt expect to see much of an effect because the amount of VEGF made inside endothelial cells was miniscule compared to the levels of VEGF created outside the cells.

However, 55 percent of the mice in the study died by 25 weeks of age, the equivalent of age 30 in humans. The other mice that were followed into old age were very ill.

Some side effects have already been identified in people taking angiogenesis inhibitors, Iruela-Arispe said. And theyve been along the lines of what were seeing in the lab.

Iruela-Arispe and her team were surprised that the higher levels of VEGF found outside the endothelial cells did not compensate for the absence of the very tiny amounts inside the cells. The miniscule amount of VEGF missing had a tremendous biological significance, she said.

Clearly there is signaling from inside the cell that is different from signaling initiated outside the cell, Iruela-Arispe said. When there is no VEGF signaling inside the cell, the endothelial cells die. The intracellular part of the VEGF signaling loop is required for cell survival. This is the first demonstration that intracellular signaling is an important event.

It had been unclear why some patients on angiogenesis inhibitors developed problems with blood clots. Iruela-Arispe said her study sheds light on one possible cause.

There is enough smoke in the sky here to make me feel there may be a fire, she said. I believe the survival function of VEGF signaling is mediated from both outside and
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