AM Production in the Cerebral Microcirculation

Cerebral endothelial cells (CECs) are the most important anatomical and functional constituents of the cerebral microcirculation. The finding of high AM production in peripheral endothelial cells made it probable that CECs could be an important source of AM in the cerebral microcirculation. However, the first report did not support this hypothesis, because Sugo et al. [1] found very low AM production by cultured bovine CECs, which was only a few percent of the AM production of rat aortic endothelial cells. Later this observation was supported by Ladoux and Frelin [2], who described weak AM mRNA expression in clones of rat CECs. It should be mentioned, however, that CECs were passaged a large number of times (10 to 20 passages) in both studies, which is known to deteriorate the original pheno-type of the primary cells.

In contrast to these experiments we have recently found unexpectedly high AM production in primary cultures of rat CECs both at the peptide and at the mRNA levels [3]. Rat CECs had about one magnitude higher AM production than was published for other primary cells. Thus, available data indicate that rat CECs have the highest rates of AM synthesis and secretion among the cells studied.

The high AM production of rat CECs was further induced by astrocyte-derived factors; significantly elevated AM production was detected in the culture medium of primary rat CECs cocultured with astrocytes or cultured in astrocyte-conditioned medium. These results suggest that the in vivo AM production may be even higher than that detected in vitro. AM production by rat CECs, however, could not be induced by cytokines, bacterial lipopolysaccharide, and thrombin, which are the most powerful inducers of AM release in peripheral endothelial cells. Our studies also revealed that AM is secreted primarily but not exclusively at the luminal (blood) side of CEC monolayers. Contrary to AM, endothelin-1, a vasoconstrictor peptide, is secreted mostly toward the abluminal (brain) side of bovine CECs.

In addition to CECs, other cellular elements of the cerebral vessels can produce AM, that is, vascular smooth muscle cells, pericytes, or even astrocytes and neurons. All of these cells, however, are on the brain side of the BBB; therefore AM production by both these cells and the choroid plexus seems more likely to contribute to the AM level of the cerebrospinal fluid. AM concentration in the cere-brospinal fluid is comparable to or lower than that in plasma, and an independent regulation of AM level in these two compartments was suggested.

In vivo an approximately 50 percent higher AM concentration was found in the jugular vein than that in the carotid artery, and similarly about a 50 percent higher AM concentration was detected in the venous plasma effluxed from the brain than that from peripheral organs [3]. Previously no significant difference was observed between AM levels in the venous blood from different organs.

These observations strongly support the in vitro findings that the cerebral circulation has an exceptionally high AM

concentration due to the significantly elevated basal AM secretion by brain endothelial cells that is induced by astrocyte-derived factors.

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