Stroke Foundation

Benign vascular malformations known as cavernomas can occur in many tissues of the body. These abnormalities are characterized by enlarged, unstable and unstructured blood vessels. Medical significance, especially cavernomas in the brain that develop in about one in two hundred people. In the brain, such growths often go unnoticed for a long time and are typically discovered as incidental findings on MRI scans. When they grow larger, they often cause non-specific symptoms such as headache or dizziness. There is a risk of brain hemorrhage from these vascular growths, which can lead to seizures, neurological deficits and even stroke. Therefore, cavernomas causing the symptoms, if possible, surgically removed from the brain.

The joint Department "Vascular Biology and Tumor Metastasis" of the Medical Faculty Mannheim of the University of Heidelberg and German Cancer Research Center scientists are investigating how blood and lymphatic vessels are newly formed in tumor diseases. "Our current findings suggest that - like in tumors - excessive and uncontrolled vascular growth leads to the formation of cavernomas," said the head of the current study, Dr. Andreas Fischer.

It was already known that the disease occurs when the endothelial cells that line all blood vessels, the gene CCM1 fails. Why this leads to the characteristic malformations was not yet known. The research team has now identified, together with colleagues from Essen and Greifswald, the central signaling pathways in endothelial cells by the loss of the CCM1 gene affected. To the disease occurring in humans can simulate very well, the researchers transplanted human endothelial cells with disabled CCM1 gene in mice. The transplanted cells subsequently grew into the typical vascular malformations. This enabled the experiments to be conducted in a mouse model of human vascular malformations. Therefore, the results can be well applied to the situation in human disease, so that for example could also be carried out drugs tests.

In a first approach, the researchers tested the anti-cancer drug sorafenib, which inhibits the formation of new blood vessels. In the transplanted mice, the substance led to a massive decrease in vascular proliferation. "We will now investigate whether we can deal with a drug in cancer medicine cavernomas in the brain without surgery," explains Dr. Andreas Fischer, the future goals of the project.

Wüstehube J, Bartol A, Liebler SS, Brütsch R, Zhu Y, Felbor U, Sure U, Augustin HG, Fischer A: Cerebral cavernous malformation protein inhibits sprouting angiogenesis CCM1 by activating Notch signaling DELTA. Proc. Natl. Acad. Sci. United States, early online edition, June 21, 2010. DOI: 10.1073/pnas.1000132107

A picture for this press release is available on the Internet at:
http://www.dkfz.de/de/presse/pressemitteilungen/2010/images/vascular-lesion.jpg

Legend: Human blood vessels in an experimental mouse model: Turning the CCM1 gene leads to the typical, disorganized appearance.