Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia.

Maiko T Uemura,Virginia M Y Lee,Takakuni Maki,Masafumi Ihara,John Q Trojanowski

doi:10.3389/fnagi.2020.00080

Abstract

Pericytes are unique, multi-functional mural cells localized at the abluminal side of the perivascular space in microvessels. Originally discovered in 19th century, pericytes had drawn less attention until decades ago mainly due to lack of specific markers. Recently, however, a growing body of evidence has revealed that pericytes play various important roles: development and maintenance of blood–brain barrier (BBB), regulation of the neurovascular system (e.g., vascular stability, vessel formation, cerebral blood flow, etc.), trafficking of inflammatory cells, clearance of toxic waste products from the brain, and acquisition of stem cell-like properties. In the neurovascular unit, pericytes perform these functions through coordinated crosstalk with neighboring cells including endothelial, glial, and neuronal cells. Dysfunction of pericytes contribute to a wide variety of diseases that lead to cognitive impairments such as cerebral small vessel disease (SVD), acute stroke, Alzheimer’s disease (AD), and other neurological disorders. For instance, in SVDs, pericyte degeneration leads to microvessel instability and demyelination while in stroke, pericyte constriction after ischemia causes a no-reflow phenomenon in brain capillaries. In AD, which shares some common risk factors with vascular dementia, reduction in pericyte coverage and subsequent microvascular impairments are observed in association with white matter attenuation and contribute to impaired cognition. Pericyte loss causes BBB-breakdown, which stagnates amyloid β clearance and the leakage of neurotoxic molecules into the brain parenchyma. In this review, we first summarize the characteristics of brain microvessel pericytes, and their roles in the central nervous system. Then, we focus on how dysfunctional pericytes contribute to the pathogenesis of vascular cognitive impairment including cerebral ‘small vessel’ and ‘large vessel’ diseases, as well as AD. Finally, we discuss therapeutic implications for these disorders by targeting pericytes.

Highlights

Pericytes are mural cells, embedded within the basement membrane, and surrounding microvessels as illustrated in Figures 1 and 2. These cells were originally described in late 19th century (Eberth, 1871; Rouget, 1873) and initially named “pericytes” in 1923 by Zimmermann (Zimmermann, 1923) in accordance with their location enveloping the endothelium, and their being embedded in the basement membrane outside the microvessels (Zimmermann, 1923; Armulik et al, 2011; Geranmayeh et al, 2019)
Microvascular pericytes in the central nervous system (CNS) have come into focus as they contribute to the maintenance of blood–brain barrier (BBB) (Armulik et al, 2010; Bell et al, 2010; Daneman et al, 2010; Quaegebeur et al, 2010), regulation of cerebral blood flow (CBF) (Peppiatt et al, 2006), and clearance of toxic waste products from the brain (Lendahl et al, 2019) as well as other multifunctional properties
Located at the interface between CNS tissue and blood circulation and having multi-functional properties, pericytes play a variety of fundamental roles in the healthy CNS

Summary

Introduction

Pericytes are mural cells, embedded within the basement membrane, and surrounding microvessels as illustrated in Figures 1 and 2. To make matters more complicated, Hill et al (2015), have asserted that the mural cells on the proximal branches coming off arterioles should be called as SMCs, which have provided confusion in the field with the result that different members of the field use different terminologies and definitions about pericytes and pericyte-residing vessels (Hartmann et al, 2015; He L. et al, 2016; Kisler et al, 2017a; Yang et al, 2017; Smyth L. et al, 2018; Dalkara, 2019; Grant et al, 2019).

Results

Conclusion