Physiology and Pathophysiology of Cerebral Microcirculation

Abstract

The brain uses more energy than any other organ in the body and relies on uninterrupted supply of glucose and oxygen via blood flow. Blood flow in human gray matter is in the range of 40-70 mL/100 mL/min and is regulated to match the metabolic demand of the brain region supplied. Majority of the nutrient and waste exchange takes place at microcirculation. Penetrating arteries supplying the brain branch into arterioles and terminate in an extensive network of capillaries. The total length of capillaries in 1 mm 3 of human cortex is about 50 cm. Unlike other organs where temporary closing or recruitment of capillaries matches the varying tissue O 2 demand, in the brain, this is likely regulated by heterogeneity of red blood cell transit times across capillaries. Increases in neuronal activity also cause an enhanced blood flow to the active brain area. This neurovascular coupling is regulated by multiple mechanisms: adenosine and lactate produced as end products of the enhanced metabolism couple neural activity with flow by inducing vasodilation. As a specific mechanism to the brain, glutamate-induced Ca 2+ increases in astrocytes, and interneurons play an important role to translate neuronal activity (assessed by monitoring glutamate released to the extracellular space) to vasoactive signals such as arachidonic acid metabolites and nitric oxide (NO). K + released onto smooth muscle cells through Ca 2+ -activated K + channels on astrocyte endfeet plasmalemma can also induce dilation during neuronal activity. Majority of the regulation takes place around arterioles. Relative contributions of the above pathways to blood flow increase vary in different brain regions. Another unique feature of cerebral circulation is the blood-brain barrier (BBB) that limits and regulates entry of blood constituents (including ions) to the CNS parenchyma. A close interaction between the endothelia and pericytes as well as astrocytes is required for development and functioning of the neurovascular unit and BBB. The ratio of pericytes to endothelial cells is much higher in the cerebral microcirculation compared to other tissues. Pericytes may play a role in distribution of microvascular blood flow depending on the very focal demand as a final step of flow regulation after the arterioles. This flow regulation with fine spatial resolution may be essential for tissues with high functional specialization such as the brain and retina. Retinal microvessels appear particularly dependent on pericytes. Pericyte loss in the retinal microvessels is a hallmark of diabetic retinopathy. The microvascular injury induced by ischemia/reperfusion plays a critical role in determining tissue survival after recanalization in focal cerebral ischemia by disrupting the blood-brain barrier integrity and inducing microcirculatory clogging (no-reflow). Radicals produced during ischemia/reperfusion afflict microvessels more heavily compared to larger vessels. Effective suppression of oxidative/nitrative stress during pharmacological or interventional reopeni...