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Pericytes of the neurovascular unit: key functions and signaling pathways

Nature Neuroscience volume 19, pages 771–783 (2016)Cite this article

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Abstract

Pericytes are vascular mural cells embedded in the basement membrane of blood microvessels. They extend their processes along capillaries, pre-capillary arterioles and post-capillary venules. CNS pericytes are uniquely positioned in the neurovascular unit between endothelial cells, astrocytes and neurons. They integrate, coordinate and process signals from their neighboring cells to generate diverse functional responses that are critical for CNS functions in health and disease, including regulation of the blood–brain barrier permeability, angiogenesis, clearance of toxic metabolites, capillary hemodynamic responses, neuroinflammation and stem cell activity. Here we examine the key signaling pathways between pericytes and their neighboring endothelial cells, astrocytes and neurons that control neurovascular functions. We also review the role of pericytes in CNS disorders including rare monogenic diseases and complex neurological disorders such as Alzheimer's disease and brain tumors. Finally, we discuss directions for future studies.

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Figure 1: The multifunctional role of CNS pericytes at the NVU.
Figure 2: PDGF-BB–PDGFRβ signaling in pericytes.
Figure 3: Deficient PDGF-BB–PDGFRβ signaling in pericytes may promote neuronal dysfunction and degeneration in Alzheimer's dementia.
Figure 4: TGF-β–TGFβR2, Notch, VEGF-A–VEGFR2, Ang–Tie2 and MFSD2A signaling pathways.
Figure 5: Pericyte–astrocyte and pericyte–neuron signaling pathways.
Figure 6: Integrated pathways between pericytes, endothelial cells and astrocytes in the NVU.

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Acknowledgements

B.V.Z. is supported by the National Institutes of Health grants R01AG023084, R01NS090904, R01NS034467 and R01AG039452 and the Cure for Alzheimer's Fund.

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  1. zlokovic@usc.edu

Authors and Affiliations

  1. Department of Physiology and Biophysics, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA

    Melanie D Sweeney & Berislav V Zlokovic

  2. Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA

    Melanie D Sweeney & Berislav V Zlokovic

  3. CytoSolve Research Division, Systems Biology Group, Cambridge, Massachusetts, USA

    Shiva Ayyadurai

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S.A. is employed by CytoSolve, Inc. which developed a software-based computational platform for scalable integration of molecular models to offer a systems biology approach to pathway analysis.

Integrated supplementary information

Supplementary Figure 1 Signal transduction pathways of endothelial cells: expanded details of ‘NVU cells’ layer in the NVU integrated pathway model.

The numbered boxes partition the cell’s downstream molecular events and the arrows between boxes illustrate interactions amongst pathways. Additional signal transduction events can be modularly incorporated into this model, as indicated in box 12. Multiple signal transduction events can promote a given function (denoted in yellow box). Specific downstream signaling mechanisms and resulting transcriptional gene expression/inhibition in endothelial cells can directly promote or inhibit signaling with pericytes (see ‘interactive signaling’ in Figure 6) that, when awry, can contribute to dysfunction in major neurological disorders (see ‘Disorders’ in Figure 6).

Supplementary Figure 2 Signal transduction pathways of pericytes: expanded details of ‘NVU cells’ layer in the NVU integrated pathway model.

The numbered boxes partition the cell’s downstream molecular events and the arrows between boxes illustrate interactions amongst pathways. Additional signal transduction events can be modularly incorporated into this model, as indicated in box 13. Multiple signal transduction events can promote a given function (denoted in yellow box). Specific downstream signaling mechanisms and resulting transcriptional gene expression/inhibition in endothelial cells can directly promote or inhibit signaling with endothelial cells or astrocytes (see ‘interactive signaling’ in Figure 6) that, when awry, can contribute to dysfunction in major neurological disorders (see ‘Disorders’ in Figure 6).

Supplementary Figure 3 Signal transduction pathways of astrocytes: expanded details of ‘NVU cells’ layer in the NVU integrated pathway model.

The numbered boxes partition the cell’s downstream molecular events and the arrows between boxes illustrate interactions amongst pathways. Additional signal transduction events can be modularly incorporated into this model, as indicated in box 2. Specific downstream signaling mechanisms and resulting transcriptional gene expression/inhibition in endothelial cells can directly promote or inhibit signaling with pericytes (see ‘interactive signaling’ in Figure 6) that, when awry, can contribute to dysfunction in major neurological disorders (see ‘Disorders’ in Figure 6).

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Sweeney, M., Ayyadurai, S. & Zlokovic, B. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci 19, 771–783 (2016). https://doi.org/10.1038/nn.4288

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