The main role in the new findings is played by a protein called tissue factor. This factor turns out to have both a stimulatory function and an inhibitory function in the generation of blood vessels. Normally these two functions neutralize each other, but in diseases like retinopathy - where unwanted blood vessels grow into the retina - this balance is disturbed. The research team shows this in an article in the May issue of Nature Medicine.
Tissue factor is found in the cell walls of endothelial cells that line the lumenal side of blood vessels. The part of the tissue factor that faces the cell exterior sends signals, in combination with a certain so-called coagulation factor, to activate blood vessel cells to generate new vessel structures. The part of the tissue factor that resides on the inside of cells sends opposing signals that inhibit cell activation.
The group has unraveled these mechanisms by using several methods. For one thing, they have managed to generate transgenic mice that lack either the inhibitory mechanism, the stimulatory mechanism, or both. The results turned out accordingly: in mice without the inhibitory mechanism, for example, they have observed abnormally rapid growth of blood vessels in the retina and in tumors.
Another discovery reported in the article involves pathologically altered blood vessels from deceased patients with diabetes retinopathy. In these vessels it could be seen that the stimulatory mechanism had been activated, whereas the inhibitory part of tissue factor had an altered structure indicating that this mechanism had been turned off. These changes may have been responsible for the occurrence of blood-vessel abnormalities associated with diabetic retinopathy.
We are now looking for substances that can attenuate these altered structures in tissue factor, says Mattias Belting. He performed his studies during his stay at the prestigious Scripps Research Institute in San Diego, and is currently heading a research team at Lund University.
Tissue factor has been known to play a major role in triggering the coagulation of blood. These new discoveries show that it is also important in the generation of new blood vessels, i.e. angiogenesis. Medication to inhibit angiogenesis is now seen as a possible way of starving cancer tumors and perhaps fatty tissue in extremely obese individuals. In other words, there are myriad avenues of research that could lead to new treatments and drugs.
Journal
Nature Medicine