Emerging Roles of Pericytes in the Regulation of the Neurovascular Unit in Health and Disease

Abstract

Pericytes of the central nervous system (CNS) are uniquely positioned within a multicellular structure termed the neurovascular unit (NVU) to provide crucial support to blood brain barrier (BBB) formation, maintenance, and stability. Numerous CNS diseases are associated with some aspect of BBB dysfunction. A dysfunction can manifest as one or multiple disruptions to any of the following barriers: physical, metabolic, immunological and transport barrier. A breach in the BBB can notably result in BBB hyper-permeability, endothelial activation and enhanced immune-endothelial interaction. How the BBB is regulated within this integrated unit remains largely unknown, especially as it relates to pericyte-endothelial interaction. We summarize the latest findings on pericyte origin, possible marker expression, and availability within different organ systems. We highlight pericyte-endothelial cell interactions, concentrating on extra- and intra- cellular signaling mechanisms linked to platelet derived growth factor-B, transforming growth factor -β, angiopoietins, Notch, and gap junctions. We discuss the role of pericytes in the NVU under inflammatory insult, focusing on how pericytes may indirectly affect leukocyte CNS infiltration, the direct role of pericyte-mediated basement membrane modifications, and immune responses. We review new findings of pericyte actions in CNS pathologies including Alzheimer’s disease, stroke, multiple sclerosis, diabetic retinopathy, and HIV-1 infection. The uncovering of the regulatory role of pericytes on the BBB will provide key insight into how barrier integrity can be re-established during neuroinflammation.

Regulation of ABC Transporters Blood–Brain Barrier

“…Finally, over the past decade it has become abundantly clear that the brain capillary endothelium is in intimate contact with other elements of the neurovascular unit (pericytes, astrocytes, neurons, and microglia), and that all elements converse (Abbott & Friedman, 2012;Hill, Rom, Ramirez, & Persidsky, 2014). We are now beginning to understand the language used in this conversation, especially with regard to the development and maintenance of the barrier's unique properties.…”

Pericytes in Brain Injury and Repair After Ischemic Stroke

“…Pericytes are a group of contractile cells that are located between ECs, astrocytes, and neurons and almost entirely embedded within the basal lamina [6]. Pericytes provide support to other NVU components and maintain the normal physiological functions of blood-brain barrier (BBB) [7–8]. Moreover, accumulating evidences suggest the importance of pericytes in the pathogenesis of cerebrovascular diseases, including stroke.…”

Differences in the molecular structure of the blood-brain barrier in the cerebral cortex and white matter: an in silico, in vitro, and ex vivo study

“…Because of the diversity in their origin, localization, and functional status, there is no unique or specific marker of this cell type. PDGF receptor-␤ (PDGFR␤), ␣-smooth muscle actin (␣SMA), chondroitin sulfate proteoglycan 4/neural-glial antigen 2 (CSPG4/NG2), pericytic aminopeptidase N (CD13), desmin, regulator of G protein signaling 5 (RGS5), and Kir 6.1 (KCNJ8, an ATP-sensitive K ϩ channel) are considered markers of brain pericytes (5,16). Among these, ␣SMA, NG2, and PDGFR␤ are the most commonly considered.…”