Central nervous system pericytes in health and disease

Abstract

Pericytes are uniquely positioned within the neurovascular unit to serve as vital integrators, coordinators and effectors of many neurovascular functions, including angiogenesis, blood-brain barrier (BBB) formation and maintenance, vascular stability and angioarchitecture, regulation of capillary blood flow and clearance of toxic cellular byproducts necessary for proper CNS homeostasis and neuronal function. New studies have revealed that pericyte deficiency in the CNS leads to BBB breakdown and brain hypoperfusion resulting in secondary neurodegenerative changes. Here we review recent progress in understanding the biology of CNS pericytes and their role in health and disease.

Figure 1

Structural and molecular pericyte connections within the neurovascular unit. Right: pericytes (green) and endothelial cells (purple) are connected to a shared basement membrane (yellow) by several types of integrin molecule. In areas lacking the basement membrane, interdigitations of pericyte and endothelial cell membranes, called peg and socket contacts, form direct connections and contain several different transmembrane junctional proteins (inset). N-cadherin is the key adherens junction protein between pericytes and endothelium. Pairs of connexin 43 (CX43) hemichannels expressed respectively in pericytes and endothelium form gap junctions that allow transfer of molecules between pericytes and endothelial cells. Adhesion plaques similar to desmosomes contain fibronectin deposits in the intercellular spaces between pericytes and endothelial cells. CX43 is also abundant at astrocyte–endothelial cell and astrocyte-neuron interfaces. Different types of tight junction proteins, tight junction adaptor proteins and adhesion junctions regulate direct endothelial cell–endothelial cell contacts forming the anatomical blood-brain barrier.

Figure 2

Origin of pericytes in the CNS. The embryonic sources of pericytes include (1) neuroectoderm-derived neural crest cells, which give rise to pericytes of the forebrain, (2) mesoderm-derived mesenchymal stem cells, which give rise to pericytes in the midbrain, brain stem and spinal cord, and (3) expansion by proliferation from the newly established pericyte pools. Postnatal sources of pericytes include (3) expansion by proliferation from the existing pericyte pools and (4) mesoderm-derived circulating mesenchymal stem cells (bone marrow pericyte progenitor cells) and presently undetermined ‘other’ sources

Figure 3

Pericyte-endothelial signaling. (a) Pericyte proliferation and migration. Endothelial cell (EC)-secreted PDGF-BB is retained within the extracellular matrix (ECM). PDGF-BB binds to PDGFRβ on the pericyte (PC) plasma membrane, leading to PDGFRβ dimerization, autophosphorylation and activation of several downstream signal transduction cascades (for example, Src, the Grb2 adaptor protein, phosphatidylinositol-3-OH kinase (PI3K), Ras GTPase activating protein (RasGAP), phospholipase C (PLC)-γ, SHP-2 tyrosine phosphatase), resulting in pericyte proliferation and cytoskeletal rearrangements facilitating migration. (b) Pericyte attachment and differentiation. In both pericytes and endothelium, TGF-β binding to TGFβR2 leads to activation of the ALK5-SMAD2/3 pathway and nuclear translocation of the Smad2/3/4 complex with unique consequences in the two cell types. In pericytes, it inhibits proliferation and leads to expression of contractile and ECM proteins. In endothelium, it also inhibits proliferation and cooperates with Notch signaling to increase expression of N-cadherin. Specifically, when Notch1 on the endothelial cell binds to an unspecified Notch ligand on the pericyte, activation leads to nuclear translocation of the Notch intracellular domain (NICD). NICD and the Smad2/3/4 complex interact with the transcription factor RBP-Jκ, promoting the upregulation of N-cadherin. Sphingosine-1 phosphate (S1P)-mediated activation of endothelial S1P1 facilitates N-cadherin trafficking to the endothelial cell membrane by the action of the GTPases RhoA and Rac1. Elevated endothelial N-cadherin leads to increased homophilic interactions with N-cadherin on pericytes, resulting in endothelial cell–pericyte adhesion. PDGF-BB/PDGFRβ signaling may also contribute to endothelial cell-pericyte attachment. However, the mechanism by which this occurs and whether N-cadherin is involved remain to be determined. (c) Pericyte survival. Activated PDGFRβ leads to activation of Akt and Erk serine/threonine kinases and downstream survival pathways. Some studies implicate Notch3 signaling in pericyte survival. (d) Endothelial maturation. Pericyte-derived TGF-β binds to TGFβR2 in endothelium and activates ALK5-Smad2/3/4 and ALK1-Smad1/5/8 pathways, exerting opposing effects on endothelial proliferation. Smad2/3/4 and angiopoietin-1 (Angpt1)/Tie2 signaling contribute to BBB formation.

Figure 4

Pericytes are multi-functional members of the neurovascular unit. Pericytes (1) control BBB integrity by regulating the orientation and abundance of endothelial tight and adherens junction proteins, as well as the rate of bulk flow fluid transcytosis (transendothelial transport of fluid-filled vesicles); (2) regulate the stability and architecture of newly formed cerebral microvessels; (3) contribute to secretion and regulate the levels of extracellular matrix proteins forming the basement membrane; (4) regulate capillary diameter and blood flow; and (5) provide clearance and phagocytotic functions in brain.

Figure 5

Pericyte loss can trigger primary vascular dysfunction leading to neurodegeneration. (a) (1) Blood-brain barrier (BBB) breakdown due to disrupted BBB tight and adherens junctions and increased bulk flow fluid transcytosis leads to brain influx of serum proteins (for example, albumin, immunoglobulin G (IgG)), causing edema, and of blood-derived vasculotoxic and neurotoxic macromolecules (for example, fibrin, thrombin, hemoglobin (Hb)-derived iron), causing neuronal injury and neurodegenerative changes. RBC, red blood cell; ROS, reactive oxygen species. (2) Reductions in capillary blood flow due to microvascular degeneration and pericapillary edema aggravate chronic hypoperfusion and hypoxia, depriving metabolically active neurons of oxygen and other essential nutrients, which leads to neuronal dysfunction. (b) Flow chart diagram depicting how deficient PDGFB/PDGFRβ signaling leads to pericyte loss resulting in (1) BBB breakdown and (2) hypoperfusion and hypoxia, as shown in a. Both arms 1 and 2 contribute to secondary neuronal degenerative changes.