One heart and one soul
The growth direction of nerve cells is strictly controlled by the organism. One of the proteins involved also appears to be involved in deciding where new blood vessels are allowed to form. This challenges our simple notion of the genesis of the circulatory system. At the same time, new approaches for the therapy of blocked blood vessels are opening up. Michael Klagsbrun of Children's Hospital and his colleagues at Harvard Medical School describe the molecular similarities of these supposedly separate organ systems in their study (Cell 20 March 1998).
Your investigation encompasses two rapidly growing research areas. One is angiogenesis - the growth of new blood vessels - which occurs mainly during development of the organism, but also in the menstrual cycle, in wound healing and in cancer. The second field looks at how the trillion neurons in the growing brain make their network of connections to one another.
The study shows that the two processes have at least one important molecule in common. The growth factor VEGF (for vascular endothelial growth factor) initiates the formation of new blood vessels that supply tumors, for example. It has been researched in Klagbrun's laboratory for the past five years. Shay Soker discovered a new receptor for the factor during this time. The name of the third known receptor for VEGF is Neuropilin-1. This protein is found in the brain and is also a receptor for ligands called collapsins or semaphorins. The collapsins/semaphorins, in turn, belong to the proteins that determine where the extensions of the nerve cells, their axons, are allowed to grow. Klagsbrun believes that these results show that VEGF is not only a growth factor for endothelial cells, but also performs other functions.
His research group discovered that cells from breast and prostate tumors synthesize large amounts of neuropilin. That seemed confusing at first. Scientists previously thought that the cancer cells secreted VEGF, which diffuses through the tissue and binds to the two previously known receptors on endothelial cells in nearby blood vessels, causing a bloodstream to form to the tumor. So what would be the point of a third receptor that is also located on the cancer cells themselves? Klagsbrun responds that according to preliminary results, VEGF can block the cell's genetically embedded suicide program.
But even more interesting is the question of what significance this connection between the growth of nerve cells and blood vessels has for embryonic development. Could it be that the network of blood vessels is built up just as carefully as our brain? "Until now no one really thought that this could be true of blood vessels. We thought you add a growth factor and the vessels grow in all directions. Now we are asking whether there is also a kind of control system for the bloodstream," says Klagsbrun.
His team is currently investigating whether neuropilin affects the direction in which blood vessels develop. They genetically engineered endothelial cells to contain neuropilin and one of the well-known VEGF receptors called KDR. Some cells had only one of the receptors on their surface, others both. The scientists found that cells with both receptors responded about twice as well to a VEGF concentration gradient as cells that only had neuropilin or KDR.
Further experiments, in which the functions of the individual components on the growth of nerve cells are tested, are being carried out in collaboration with Jonathan Raper of the University of Pennsylvania. Many questions are still open. However, the researchers hope that their results will later initiate the growth of blood vessels around blockages and prevent nerve cells from dying after a stroke.
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