In most regions of brain, tight junctions are present between adjacent endothelial cells. These cells, which constitute the blood-brain barrier (BBB), do not express/ possess fenestrations, contain few pinocytotic vesicles, and exhibit very high transendothelial electrical resistance. These unique features are due in very large part to induction of BBB properties by astrocytes. Once induced during later embryological development, the BBB plays many important functions including protecting the brain from fluctuations in changes in concentrations of ions, neurotransmitters, and other substances that could affect neuronal and/or glial function. The genomic and proteomic expression patterns that account for these unique characteristics are only beginning to be defined. Recent studies have begun to explain at the molecular level how permeability of the BBB is regulated. For example, studies in gene-targeted mice have shown that deficiency in claudin-5 (a major cell adhesion protein expressed within endothelium and at tight junctions) increases permeability of the BBB to small molecules.
In addition to the presence of tight junctions between cells, the BBB exhibits other unique permeability characteristics. While the BBB is very selective in relation to substances are allowed to pass from blood to brain, it also expresses a host of transporters for key substances such as glucose and some amino acids.
Many studies have examined the pathophysiology of changes in permeability of the BBB. This work has identified veins and venules as major sites of disruption of the barrier, and found that many conditions (including ischemia with reperfusion, acute hypertension, proinflammatory stimuli, subarachnoid hemorrhage, and meningitis) disrupt the BBB. Although several mechanisms may by involved, a common mediator of this disruption in disease states may be reactive oxygen or reactive nitrogen species (see later discussion).
In contrast to most regions of the brain, some sites within the central nervous system do not have tight junctions between endothelial cells. These sites include the choroid plexus, which is the major site of formation of cere-brospinal fluid (CSF), and the circumventricular organs. Resting levels of blood flow and microvascular permeability within these regions are very high compared to regions expressing the BBB. Regulation of blood flow is also unique in these structures. For example, humoral stimuli such as circulating angiotensin II and vasopressin have marked effects on blood flow to choroid plexus and production of cerebrospinal fluid but little effect on blood flow to other regions of the brain.
The cerebral microcirculation is also unique in that resistance of large arteries appears to be greater in the cerebral circulation than in other vascular beds. Large arteries contribute importantly to total cerebral vascular resistance and are major determinants of local microvascular pressure (arteriolar pressure), which is lower than in other vascular beds.
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