Central Nervous System Pericytes Contribute to Health and Disease

Abstract

Successful neuroprotection is only possible with contemporary microvascular protection. The prevention of disease-induced vascular modifications that accelerate brain damage remains largely elusive. An improved understanding of pericyte (PC) signalling could provide important insight into the function of the neurovascular unit (NVU), and into the injury-provoked responses that modify cell-cell interactions and crosstalk. Due to sharing the same basement membrane with endothelial cells, PCs have a crucial role in the control of endothelial, astrocyte, and oligodendrocyte precursor functions and hence blood-brain barrier stability. Both cerebrovascular and neurodegenerative diseases impair oxygen delivery and functionally impair the NVU. In this review, the role of PCs in central nervous system health and disease is discussed, considering their origin, multipotency, functions and also dysfunction, focusing on new possible avenues to modulate neuroprotection. Dysfunctional PC signalling could also be considered as a potential biomarker of NVU pathology, allowing us to individualize therapeutic interventions, monitor responses, or predict outcomes.

Keywords: Alzheimer’s disease; angiogenesis; mesoangioblast; multiple sclerosis; neuroCOVID-19; neurodevelopmental disorders; neuroinflammation; neurovascular unit; stroke.

Figure 1

(A) A schematic depiction of NVU components from axial and longitudinal views: endothelial cell (EC), pericyte (PC), perivascular basement membrane (BM), and astrocytes (A), vessel-associated microglial cells (mG), OPCs/NG2-glia, macrophages, axon terminals (AT) which can contact EC. The longitudinal drawing shows mural cell types along the CNS vasculature without considering the presence of continuous BM between ECs and PCs. Smooth muscle cells wrap the arterioles, forming multiple concentric rings in continuity with hybrid smooth-muscle-PCs residing along the precapillary arterioles, which appear to join to ensheathing PCs at the arteriole–capillary interface. PCs in microvessels typically exhibit two phenotypes: the mesh PC characterized by short ramified processes, versus the thin-strand PC with long processes embracing the microvessel in a single strand, or helically twisted strand pairs. Mesh PCs prevail at the capillary–postcapillary venule interface. Stellate-shaped smooth muscle cells are present around parenchymal venules. (B) The mesh PC fine morphology and microvascular basal lamina relationships are shown in a representative vessel of the dorsal wall of the telencephalic vesicles (forebrain, future neocortex) of a 22-week-old human foetus. The extensive PC coverage and its relation to the collagen VI-enriched basal lamina is highlighted by an NG2/CSPG4 isoform, specifically recognized by the antibody 2161D7, that outlines not only the finer cell details such as the dense net of finger-like processes, but also the abluminal bumpy surface of the PC body (arrow) at the branching point. (C) The same 2161D7 antibody, recognizing an NG2/CSPG4 isoform expressed by foetal brain PCs, weakly stains just the PC body (arrow) of the adult human parahippocampal cortex. Other monoclonal antibodies against NG2 isoforms and commercial antibodies do not stain human adult CNS PCs [19]. Nuclear counterstaining TO-PRO3. Bars B, C: 10 µm.

Figure 2

A schematic depiction of NVU components in Alzheimer’s disease (AD). The pericyte (PC) and astrocyte (AC) endfeet both appear detached from the vessel lumen, the perivascular basement membrane (BM) is thickened and vessel-associated microglial cells (mG) and macrophages (Mp) induce neuroinflammation. Dysfunctional PCs also release pro-inflammatory molecules and reduce the trophic support to oligodendrocyte precursor cells (OPCs)/NG2-glia. Altogether, these dysfunctions induce vascular damage and a reduced cerebral blood flow (CBF), acting via altered amyloid precursor protein (APP) proteolysis and consequent amyloid β accumulation inducing synaptic dysfunction and neuronal loss.

Figure 3

A schematic depiction of NVU components in a chronic end-stage MS lesion dominated by hypoperfusion and a persistent inflammatory milieu with abundant reactive oxygen species (ROS, O₂₋), peroxynitrite (NO₃₋). Vessel-associated microglial cells, monocytes, macrophages (Mp) and autoantibodies induce persistent neuroinflammation, also responsible for pericyte (PC) dysfunctions. PCs release pro-inflammatory molecules and reduce the trophic support to oligodendrocyte precursor cells (OPCs)/NG2-glia. The drawing also shows the inflammatory influence of demyelination on reduced axonal activities and vasoconstriction. Hypoperfusion is also attributable to vessel wall hyalinization, collagen deposition and astrocyte endfeet hypertrophy.

Figure 4

A schematic depiction of NVU components in a stroke lesion dominated by BBB leakiness, vasogenic swelling of BM, cytotoxic oedema, a PC hypercontracted state, astrocyte endfeet detachment from PCs, and completely disrupted NVU interactions: the TJ proteins claudin-5 and occludin are damaged and EC apoptosis is frequently observed; the BM is degraded by MMPs, mainly released by leukocytes infiltrating vessel BM and PCs enwrapping altered endothelial cells; large amounts of pro-inflammatory mediators and fibrin(ogen) derive from the blood stream, but additional harmful inflammatory molecules are released by PCs.