The role of pericytes in brain disorders: from the periphery to the brain

Abstract

It is becoming increasingly apparent that disorders of the brain microvasculature contribute to many neurological disorders. In recent years it has become clear that a major player in these events is the capillary pericyte which, in the brain, is now known to control the blood–brain barrier, regulate blood flow, influence immune cell entry and be crucial for angiogenesis. In this review we consider the under‐explored possibility that peripheral diseases which affect the microvasculature, such as hypertension, kidney disease and diabetes, produce central nervous system (CNS) dysfunction by mechanisms affecting capillary pericytes within the CNS. We highlight how cellular messengers produced peripherally can act via signalling pathways within CNS pericytes to reshape blood vessels, restrict blood flow or compromise blood–brain barrier function, thus causing neuronal dysfunction. Increased understanding of how renin–angiotensin, Rho‐kinase and PDGFRβ signalling affect CNS pericytes may suggest novel therapeutic approaches to reducing the CNS effects of peripheral disorders.

Impact of the Renin–Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

“…Pericytes are multifunctional mural cells located within the basement membrane of microvessels and adjacent to endothelial cells. Pericytes are abundantly present along the walls of brain microvasculature, including pre-capillary arterioles, capillaries, and post-capillary venules, and are a vital component of the neurovascular unit [ 70 ]. Studies have reported key roles of pericytes in the regulation of the BBB integrity, modulation of cerebral blood flow, central nervous system scarring, migration of white blood cells through the vascular wall, and promoting angiogenesis and clearance of cell debris [ 70 , 71 , 72 ].…”

“…Additionally, diabetes-induced advanced glycation end-product formation enhances fibronectin production in pericytes with associated basement membrane hypertrophy and downregulates claudin-5 expression in microvascular CEC via VEGF and MMP2, thus promoting tight junction damage [ 76 ]. Moreover, kidney diseases can increase the rate of calcification and mineralization in pericytes and modify their function [ 70 ].…”

“…The renin–angiotensin system, a contributor to the pathophysiology of hypertension, diabetes and kidney disease, can alter the function of CNS pericytes [ 70 ]. RT-PCR using RNA from human brain pericytes confirmed that both AT1R and AT2R are expressed with a predominant expression of AT1R [ 71 ].…”

“…AT1R also mediates the Ang II-induced influx of calcium to retinal pericytes, and the constriction of the underlying capillaries. The consequent depletion of NO and increase of oxidative stress can also disrupt the endothelium-dependent vasodilation [ 70 ].…”

“…In the same context, the interaction between PDGFR-BB and PDGFRβ is crucial for the maintenance of the blood–brain barrier. The absence of either PDGF-BB (released by endothelial cells) or PDGFRβ (the corresponding receptor on pericytes) leads to pericyte loss and blood–brain barrier compromise [ 70 ].…”