Establishing the structure, regulation, and conservation of endothelial “kugeln”

Understanding how the cerebral vessels form may provide insight into human diseases such as stroke and dementia. We discovered a novel endothelial behaviour in the cerebral vessels of zebrafish. These develop transient, large spherical membrane protrusions with no luminal communication that we named “kugeln”.

Kugeln develop in the absence of blood flow, contain little or no cytoplasm and are highly reactive for Nitric Oxide. Our pilot data suggest both chicken embryonic and adult mice brains contain kugeln.

Since kugeln are restricted to cerebral vessels and are Notch-dependent, they may provide new insights into specific features of cerebrovascular development.

Kugeln may also be relevant to CADASIL, the commonest genetic cause of stroke which is caused by Notch3 receptor mutations.

We will determine the ultrastructure of kugeln, whether they are present on the cerebral vessels of chickens, mice and humans (including CADASIL patients) and the effect of genetic manipulation of the notch pathway on kugeln biogenesis in zebrafish. Our findings will extend our understanding of this unprecedented endothelial cell behaviour.