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Review
. 2014 Apr 16;15(4):6453-74.
doi: 10.3390/ijms15046453.

The role of pericytes in neurovascular unit remodeling in brain disorders

Ayman ElAli  1 , Peter Thériault  2 , Serge Rivest  3
Affiliations
Review

The role of pericytes in neurovascular unit remodeling in brain disorders

Ayman ElAli et al. Int J Mol Sci. .

Abstract

Neurons are extremely vulnerable cells that tightly rely on the brain's highly dynamic and complex vascular network that assures an accurate and adequate distribution of nutrients and oxygen. The neurovascular unit (NVU) couples neuronal activity to vascular function, controls brain homeostasis, and maintains an optimal brain microenvironment adequate for neuronal survival by adjusting blood-brain barrier (BBB) parameters based on brain needs. The NVU is a heterogeneous structure constituted by different cell types that includes pericytes. Pericytes are localized at the abluminal side of brain microvessels and contribute to NVU function. Pericytes play essential roles in the development and maturation of the neurovascular system during embryogenesis and stability during adulthood. Initially, pericytes were described as contractile cells involved in controlling neurovascular tone. However, recent reports have shown that pericytes dynamically respond to stress induced by injury upon brain diseases, by chemically and physically communicating with neighboring cells, by their immune properties and by their potential pluripotent nature within the neurovascular niche. As such, in this paper, we would like to review the role of pericytes in NVU remodeling, and their potential as targets for NVU repair strategies and consequently neuroprotection in two pathophysiologically distinct brain disorders: ischemic stroke and Alzheimer's disease (AD).

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Figures

Figure 1.
Figure 1.
The role of pericytes at the neurovascular unit (NVU) in the healthy brain. The NVU is constituted by specialized endothelial cells, which form the blood-brain barrier (BBB), that actively interact with the basal lamina, pericytes, astrocyte-endfeet, microglia and neurons. The pericytes play an important role in maintaining NVU physiological functions by controlling tight junction (TJ) protein expression and BBB induction, microvascular stability and microvessel diameter. Pericytes might act as pluripotent cells and might have immune function at the NVU.
Figure 2.
Figure 2.
Pericyte physical and biochemical interactions at the NVU. Pericytes are embedded within the basal lamina structure and project elongated processes that wrap endothelial cells, thus establishing specialized cell-cell contacts. These contacts are mainly from peg-socket types, where cell-cell contacts are established when pericyte cell membrane protrusion-like structures (pegs) are inserted into endothelial cell membrane invaginations (pockets) cells (outlined by dashed circles). The peg-socket contacts contain cell-to-cell junction proteins, such as N-cadherin and CX43 hemichannels. CX43 hemichannels form gap junctions that allow the biochemical exchange between pericytes and endothelial cells. In parallel, several autocrine and paracrine signaling pathways govern the interaction between pericytes and endothelial cells, such as the PDGFBB/PDGFRβ signaling pathway (paracrine pathway: PDGFBB secreted by endothelial cells binds to PDGFRβ expressed on pericytes), the TGFβ signaling pathway (paracrine and autocrine pathway: TGFβ secreted by endothelial cells and pericytes binds to TGFβR2 expressed on both cell types), the Ang1/Tie2 signaling pathway (paracrine pathway: Ang1 is secreted by pericytes binds to Tie2 expressed on endothelial cells), and the Notch signaling pathway (cleavage-induced signaling pathway: the sequential proteolytic cleavage and release in the intracellular space of the Notch intracellular domain (NICD) that translocates to the nucleus and controls downstream gene expression).
Figure 3.
Figure 3.
Pericyte responses upon NVU remodeling in ischemic stroke. Upon stroke, the ischemic cascade induces NVU remodeling that causes its loss of function, thus leading to the accumulation of blood-borne molecules into the brain. This loss of function is translated by (a) an impaired rCBF; (b) astrocyte-endfeet detachment; (c) pericyte detachment and migration; (d) microglia activation; (e) vasoconstriction and (f) pericyte contraction. Targeting NVU remodeling, in order to repair, stabilize and restitute the function of the NVU, constitutes a novel approach in developing successful strategies for treating ischemic stroke. This could be achieved by enhancing pericyte survival and in parallel by decreasing their contractility.
Figure 4.
Figure 4.
Pericyte responses upon NVU remodeling in Alzheimer’s disease (AD). In AD, the neurodegenerative cascade has been shown to be initiated by NVU remodeling that triggers its loss of function, leading to the accumulation of blood-borne molecules into the brain. This loss of function is translated by (a) rCBF dysfunction; (b) astrocyte-endfeet detachment; (c) pericyte detachment and migration; (d) microglia activation and (e) pericyte loss. Targeting NVU remodeling in order to repair, stabilize and restitute the function of the NVU, would constitute a novel approach in developing successful strategies for treating AD.
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