Journal
CURRENT NEUROVASCULAR RESEARCH
Volume 16, Issue 4, Pages 291-300Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1567202616666191014120156
Keywords
Radial glia-endothelial cells; cerebral cortex; neural stem cell; astrocytes; blood-brain barrier; isolated microcapillary brain endothelial cells; vascular development; gliogenesis
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Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [482719/2013-3]
- Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) [E26/111.449/2013]
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Background: In the developing cerebral cortex, Radial Glia (RG) multipotent neural stem cell, among other functions, differentiate into astrocytes and serve as a scaffold for blood vessel development. After some time, blood vessel Endothelial Cells (ECs) become associated with astrocytes to form the neurovascular Blood-Brain Barrier (BBB) unit. Objective: Since little is known about the mechanisms underlying bidirectional RG-ECs interactions in both vascular development and astrocyte differentiation, this study investigated the impact of interactions between RG and ECs mediated by secreted factors on EC maturation and gliogenesis control. Methods: First, we demonstrated that immature vasculature in the murinc embryonic cerebral cortex physically interacts with Nestin positive RG neural stem cells in vivo. Isolated Microcapillary Brain Endothelial Cells (MBEC) treated with the conditioned medium from RG cultures (RG-CM) displayed decreased proliferation, reduction in the protein levels of the endothelial tip cell marker Delta-like 4 (Dll4), and decreased expression levels of the vascular permeability associated gene, plasmalemma vesicle-associated protein-1 (PLVAP1). These events were also accompanied by increased levels of the tight junction protein expression, zonula occludens-1 (ZO-1). Results: Finally, we demonstrated that isolated RG cells cultures treated with MBEC conditioned medium promoted the differentiation of astrocytes in a Vascular Endothelial Growth Factor-A (VEGF-A) dependent manner. Conclusion: These results suggest that the bidirectional interaction between RG and ECs is essential to induce vascular maturation and astrocyte generation, which may be an essential cell-cell communication mechanism to promote BBB establishment.
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