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Abstract

During central nervous system (CNS) development, extensive reciprocal interactions exist between different cell types, including neural progenitors, neurons, endothelial cells, microglia and other glial cells that are crucial in driving proper development. Moreover, neurons and vessels share striking anatomical and molecular features and are presumably orchestrated by an overlapping repertoire of signaling systems. Here, we identify an important neuron/vessel/glia-interaction essential for the correct formation of the neurovascular system in the CNS that involves the CD95 receptor and ligand system. Deletion of CD95 receptor in neurons, as shown before, and in endothelial cells result in aberrant branching and growth of both cell types in the postnatal CNS. Furthermore, we identify microglia as the main source of CD95L and microglial-specific deletion thereof impairs proper neurovascular development. CD95 promotes endothelial cell branching and proliferation by acting as a receptor tyrosine kinase that upon activation leads to recruitment of SFK and p85 which further elicit Akt and Erk signaling, two effectors that are crucial in regulating endothelial cell growth. These data highlight a coordinated neurovascular development instructed by microglial-derived CD95L and impact the importance of microglia for the establishment of the neurovascular network during CNS development. In tumorigenesis, angiogenesis is reactivated and takes place extensively to support tumor cell growth. Glioblastoma multiforme (GBM), the most aggressive and deadly type of tumor in the brain, is characterized by a high level of angiogenesis. The CD95 receptor and ligand system also fosters tumor angiogenesis. However, this does not occur by direct activation of CD95 on endothelial cells, but rather results from CD95 activation on GBM cells. Activation of CD95 on GBM cells by CD95L leads to an increase in the release of pro-angiogenic factors that promote vessel growth in the tumor. Together, our data demonstrate a novel role of CD95 in angiogenesis both during development and tumorigenesis and show a potential to target CD95 in neurovascular diseases or tumor angiogenesis.