Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease

Abstract

Because regional blood flow increases in association with the increased metabolic demand generated by localized increases in neural activity, functional imaging researchers often assume that changes in blood flow are an accurate read-out of changes in underlying neural activity. An understanding of the mechanisms that link changes in neural activity to changes in blood flow is crucial for assessing the validity of this assumption, and for understanding the processes that can go wrong during disease states such as ischaemic stroke. Many studies have investigated the mechanisms of neurovascular regulation in arterioles but other evidence suggests that blood flow regulation can also occur in capillaries, because of the presence of contractile cells, pericytes, on the capillary wall. Here we review the evidence that pericytes can modulate capillary diameter in response to neuronal activity and assess the likely importance of neurovascular regulation at the capillary level for functional imaging experiments. We also discuss evidence suggesting that pericytes are particularly sensitive to damage during pathological insults such as ischaemia, Alzheimer's disease and diabetic retinopathy, and consider the potential impact that pericyte dysfunction might have on the development of therapeutic interventions and on the interpretation of functional imaging data in these disorders.

Keywords: brain; capillary; neurovascular coupling; pericyte.

Figure 1

Organisation of the capillary neurovascular unit. (A) Rings of smooth muscle encircle arterioles, while pericytes send processes along and around capillaries, without fully covering the vessel. (B) Pericytes are located outside the endothelial cells and are separated from them and the parenchyma by a layer of basal lamina. In the parenchyma, astrocyte end-feet and neuronal terminals are closely associated with the capillary.

Figure 2

Mechanisms of control of capillary tone. (A) Molecular mechanisms that link vasoactive molecules acting on receptors (labelled “R”) to pericyte constriction (yellow and orange shapes) or dilation (blue shapes). Rectangles are membrane proteins, while ovals are cytosolic species. SK_Ca, small conductance, calcium-activated potassium channel; BK_Ca, large conductance, calcium-activated potassium channel; K_IR, inwardly rectifying potassium channel; K_V, voltage-gated potassium channel; K_ATP, ATP-sensitive potassium channel; Cl_Ca, calcium-activated chloride channel; NSC, non-specific cation channels; R, ligand-binding receptor; VOCC, voltage-operated calcium channel; MLC, myosin light chain; αSMA, alpha smooth muscle actin; MLCK, myosin light chain kinase; CaM, calmodulin; RhoK, Rho kinase; sGC, soluble guanylyl cyclase; PKG, protein kinase G; AC, adenylyl cyclase; PKA, protein kinase A; MLCP, myosin light chain phosphatase; ET-1, endothelin-1; IGF-1, insulin-like growth factor 1; PDGF-B, platelet-derived growth factor-B; PGI₂, prostacyclin. (B) When there is a plentiful supply of O₂ and ATP, stimuli such as lactate, PDGF-B and intracellular ATP favour pericyte constriction. GJ, gap junction; PDGFβR, PDGF-B receptor. (C) When O₂ and/or ATP are low, lactate, PDGF-B and high intracellular ADP levels favour dilation.

Figure 3

Alterations in pericyte function in disease states. (A) In Alzheimer's disease, β-amyloid removal across the blood-brain barrier slows so β-amyloid aggregates are formed around blood vessels. β-amyloid is toxic to pericytes and produces superoxide (O₂•⁻), which scavenges NO, forming peroxynitrite (ONOO⁻) and constricting vessels. (B) After cerebral ischaemia, the energy supply to an ischaemic region is not fully restored as many capillaries fail to reperfuse due to blockade by polymorphonuclear leukocytes, generation of reactive oxygen species and capillary constriction. (C) In diabetic retinopathy, high glucose levels trigger pericyte apoptosis and capillary malfunction via activation of protein kinase C δ (PKCδ) and p38α mitogen activated protein kinase (p38αK). Reactive oxygen species (ROS) are generated, producing apoptosis via nuclear factor κB (NF-κB) activation and Src homology-2 domain-containing phosphatase-1 (SHP-1) is activated, which inhibits PDGFR-β, decreasing activity of pro-survival pathways and further promoting apoptosis.