Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

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.

How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke

“…In mice, pericyte ablation promotes BBB permeability and causes BBB disruption [ 17 , 47 ]. During angiogenesis, pericytes and endothelial cells cooperatively play an essential role in forming and stabilizing new blood vessels via several signaling factors, such as platelet-derived growth factor subunit B (PDGFB)/platelet-derived growth factor receptor-beta (PDGFRβ), transforming growth factor β, Notch, and vascular endothelial growth factor [ 48 ].…”

“…These findings indicate that pericytes have an important role in modulating inflammatory cells under inflammatory conditions such as after ischemic stroke. The effects of brain pericytes on inflammatory cells are not fully elucidated; however, pericytes secrete various factors (e.g., cytokine and chemokine) that can modulate the traits of macrophage/microglia into anti-inflammatory types [ 48 ]. Thus, the presence of pericytes may promote phenotypic change of macrophage/microglia into the anti-inflammatory M2 type.…”

Structural and Functional Remodeling of the Brain Vasculature Following Stroke

“…This was demonstrated by genetic ablation of pericytes resulting in loss of pleiotrophin (PTN) expression; PTN is a pericyte-secreted growth factor and loss of this factor contributed to neuronal death in this study (Nikolakopoulou et al, 2019). Hence, pericytes can play a detrimental role in ischemia-reperfusion injury and thus represent a promising therapeutic target, as reviewed elsewhere (Cai et al, 2017;Su et al, 2019;Uemura et al, 2020).…”

Advancing medicine for Alzheimer’s disease: A plasma neural exosome platform

“…Some of the vascular disturbance in early AD is attributable to capillary constriction by Aβ peptide stimulation of pericytes, that contract in response to released endogenous endothelin-1 and may begin to degenerate. 38,39…”