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Angiogenic responses in a 3D micro-engineered environment of primary endothelial cells and pericytes

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Abstract

Angiogenesis plays a key role in the pathology of diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. Understanding the driving forces of endothelial cell migration and organization, as well as the time frame of these processes, can elucidate mechanisms of action of important pathological pathways. Herein, we have developed an organ-specific microfluidic platform recapitulating the in vivo angiogenic microenvironment by co-culturing mouse primary brain endothelial cells with brain pericytes in a three-dimensional (3D) collagen scaffold. As a proof of concept, we show that this model can be used for studying the angiogenic process and further comparing the angiogenic properties between two different common inbred mouse strains, C57BL/6J and 129S1/SvlmJ. We further show that the newly discovered angiogenesis-regulating gene Padi2 promotes angiogenesis through Dll4/Notch1 signaling by an on-chip mechanistic study. Analysis of the interplay between primary endothelial cells and pericytes in a 3D microfluidic environment assists in the elucidation of the angiogenic response.

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All data generated or analyzed during this study are included in this article (and its supplementary information files), and are available from the corresponding author upon request.

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Funding

This study was supported, in part, by the NIH National Eye Institute. Award Number R01EY012726-12 (to RJD).

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Authors and Affiliations

  1. The Vascular Biology Program and Department of Surgery, Harvard Medical School, Boston Children’s Hospital, Boston, MA, USA

    Jing Bai, Mehrdad Khajavi, Lufei Sui, Haojie Fu, Subrahmanian Tarakkad Krishnaji, Amy E. Birsner, Lauren Bazinet & Robert J. D’Amato

  2. Department of Ophthalmology, Harvard Medical School, Boston, MA, USA

    Robert J. D’Amato

  3. Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Jing Bai & Roger D. Kamm

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  1. Jing Bai
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  2. Mehrdad Khajavi
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  3. Lufei Sui
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  4. Haojie Fu
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  9. Robert J. D’Amato
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Contributions

JB, RJD, MK, HJF, STK, and AEB contributed to the design and implementation of the research, JB, LFS, and LB performed the experiments, and JB, RJD, RDK, and MK contributed to the interpretation of the results and the preparation of the manuscript. All authors provided critical feedback and helped shape the research, analysis, and manuscript.

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Correspondence to Jing Bai.

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The author(s) declare(s) that there is no conflict of interest regarding the publication of this article.

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All animal studies were conducted in compliance with the protocols approved by the Institutional Animal Care and Use Committee of Boston Children’s Hospital (approval number 15-08-2998R for mouse experiments).

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Bai, J., Khajavi, M., Sui, L. et al. Angiogenic responses in a 3D micro-engineered environment of primary endothelial cells and pericytes. Angiogenesis 24, 111–127 (2021). https://doi.org/10.1007/s10456-020-09746-6

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