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Radial Glia Cells Control Angiogenesis in the Developing Cerebral Cortex Through TGF-β1 Signaling

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Abstract

Neuroangiogenesis in the developing central nervous system is controlled by interactions between endothelial cells (ECs) and radial glia (RG) neural stem cells, although RG-derived molecules implicated in these events are not fully known. Here, we investigated the role of RG-secreted TGF-β1, in angiogenesis in the developing cerebral cortex. By isolation of murine microcapillary brain endothelial cells (MBECs), we demonstrate that conditioned medium from RG cultures (RG-CM) promoted MBEC migration and formation of vessel-like structures in vitro, in a TGF-β1-dependent manner. These events were followed by endothelial regulation of GPR124 and BAI-1 gene expression by RG-CM. Proteome profile of RG-CM identified angiogenesis-related molecules IGFBP2/3, osteopontin, endostatin, SDF1, fractalkine, TIMP1/4, Ang-1, pentraxin3, and Cyr61, some of them modulated by TGF-β1 induction. In vivo gain and loss of function assays targeting RG cells demonstrates a specific TGF-β1-dependent control of blood vessels branching in the cerebral cortex. Together, our results point to TGF-β1 signaling pathway as a potential mediator of the RG-EC interactions and shed light to the key role of RG in paving the brain vascular network.

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Acknowledgements

We thank Marcelo Meloni and Adiel Batista do Nascimento for technical assistance. We also thank Dr. Dennis Grab from The Johns Hopkins University that kindly provided us with the HBMECs.

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  1. Michele Siqueira and Daniel Francis contributed equally.

Authors and Affiliations

  1. Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Michele Siqueira, Daniel Francis, Diego Gisbert, Flávia Carvalho Alcantara Gomes & Joice Stipursky

  2. Laboratório de Neurobiologia Celular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro - Centro de Ciências da Saúde, Bloco F, Sala F15, Ilha do Fundão, Rio de Janeiro, RJ, 21949-902, Brazil

    Joice Stipursky

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Contributions

M.S. and D.F. performed MBEC isolation, morphological and functional characterization, RT-PCR and RT-qPCR, Matrigel assays, RG-EC interaction experiments, and Proteome analysis. D.G. produced migration, FAK, Dll4, and TGF-β1 signaling analysis in MBEC, and VEGF expression data on RG cells. F.C.A.G. contributed to data analysis, interpretation, and paper writing. J.S. performed in vivo IUE and IV experiments and data analysis, analyzed all the data, designed the entire project and experimental approaches, and wrote the paper.

Corresponding author

Correspondence to Joice Stipursky.

Ethics declarations

All animal protocols were approved by the Animal Research Committee of the Federal University of Rio de Janeiro (DAHEICB024 and CEUA 041/14).

Competing Interests

The authors declare that they have no conflict of interest.

Funding

This work was supported by grants from: Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (J.S.; F.C.A.G.) and Conselho Nacional para o Desenvolvimento Científico e Tecnológico (J.S.; F.C.A.G.; S.M.; D.F.).

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Siqueira, M., Francis, D., Gisbert, D. et al. Radial Glia Cells Control Angiogenesis in the Developing Cerebral Cortex Through TGF-β1 Signaling. Mol Neurobiol 55, 3660–3675 (2018). https://doi.org/10.1007/s12035-017-0557-8

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