Cerebral Microcirculation

Introduction

Research on microcirculation has led to an unprecedented progress with help of amazing developments in imaging technology. It is now possible to image capillaries with high resolution down to the depths of cortex, measure O ₂ saturation and tension in them, track fast erythrocyte movements, and study Ca ²⁺ signaling, vascular diameter changes, and neurovascular coupling in wild-type as well transgenic animals expressing a large variety of reporter or actuator proteins. Not unexpectedly, it emerges that microvasculature is a complex system evolved to optimally deliver O ₂ , glucose, and other nutrients to match the local need of the surrounding tissue. Its function is regulated by even more complex mechanisms. This progress has been complemented with discovery of surprisingly important roles of microcirculation in brain diseases. The present review will briefly outline some of these developments primarily in the context of stroke and microvascular dysfunction.

Anatomy and Physiology of Microcirculation

Several arteries penetrate into the brain tissue after originating from the pial arterial/arteriolar network covering the brain surface. The penetrating arteries branch into arterioles and then to a network of capillaries. CNS capillaries are composed of a single layer of endothelium surrounded by a continuous basement membrane and are covered by astrocyte end feet over the abluminal wall ( Fig. 2.1 ). Endothelial cells are connected by tight junction proteins and form the blood–brain barrier (BBB), limiting and regulating the access of solutes to the CNS. Smooth muscle cells on arterioles are replaced by pericytes positioned between the two layers of basement membrane on capillaries . The capillary density varies to match the regional metabolic demand and is correlated with synaptic density; hence, it is higher in the cortex than in the subcortical areas. It is estimated that the mean capillary size in human cortex is 6.5 μm in diameter and 53.0 μm in length. CNS capillaries form interconnected loops to adequately supply the tissue by passive O ₂ diffusion ( Fig. 2.2 ). Capillaries are not found around large vessels (Pfeifer space); this area is directly oxygenated by diffusion of O ₂ from the large vessel (Krogh tissue cylinder) . Studies in the intact mouse brain show that, during baseline activity, arterioles provide 50% of the total extracted O ₂ , whereas the majority of the remaining O ₂ is extracted from the first few capillary branches, which is followed by recruitment of high-branching-order capillaries during activation . It should be noted that capillary segments are not linearly aligned but form loops that bring low- and high-branching-order segments in proximity such that their supply territories can interact ( Fig. 2.2 ).

The pressure gradient between the arterial and venous sides drives the microcirculatory flow. The venous outflow pressure is in equilibrium with the intracranial pressure. Accordingly, microcirculatory flow and tissue oxygenation can be adversely affected by high intracranial pressure as well as reduced arterial pressure. All cerebral capillaries are perfused by red blood cells (RBCs) and plasma under physiological conditions. The RBC velocity in capillaries is highly variable (around 0.2–4.4 mm/s). Random variations in RBC velocity including occasional stalls are observed in experimental animals under resting conditions. Capillary transit times of RBCs therefore significantly vary between neighboring branches of the network. A high capillary transit time heterogeneity (CTH) decreases the efficiency of O ₂ transfer from RBCs . The variability in transit times is reduced on neuronal activation, allowing more O ₂ to be extracted. Although debated, it appears so that, to match the very focal demand by a small group of nearby cells, the cerebral microvascular blood flow requires a final step of regulation after the arterioles, which serve a larger cohort of cells . In addition to the enhanced perfusion in dilated arterioles during neuronal activity, pericyte relaxation as well as the vasodilatory stimulus provided by ATP released from shear-stressed RBCs may reduce the microvascular resistance and promote the RBC transit. Also, the capillary endothelial surface is covered by a 0.5-μm-thick glycocalyx that facilitates the passage of blood cells and, when damaged, disrupts capillary flow.

Pericytes express several vasoactive receptors, suggesting that they have the capacity to respond to neurotransmitters and vasoactive mediators released from nearby neurons and astrocytes. Indeed, in vivo studies with two-photon microscopy have shown that cortical capillaries dilated about 1 s before arterioles during sensory stimulation in mice under anesthesia, supporting the view that capillaries may play a direct role in flow regulation . Capillary endothelia, pericytes communicating with them, and astrocyte end-feet surrounding capillaries can transmit dilatory signals to the upstream arteriole through gap junctions between them to promote arteriolar dilation for providing the blood volume increase in microcirculation .