Summary

AM seems to be an important hormone in the cerebral circulation. The concentration of AM is approximately 50 percent higher here than in other regional circulations because of the astrocyte-induced elevated AM production of CECs. AM causes vasodilation in the cerebral circulation and may be important in the maintenance of the resting cerebral blood flow and protective against ischemic brain injury. Recent data from our laboratory indicate that AM, as an endothelium-derived autocrine/paracrine hormone, plays an important role in the regulation of specific BBB properties. AM can be one of the physiological links between astrocyte-derived factors, cAMP, and the induction and maintenance of the BBB. Moreover, the role of AM in the differentiation and proliferation of peripheral endothelial cells and in angiogenesis suggests a more complex function for AM in the cerebral circulation and in the development of the BBB.

Glossary

Gs: A G protein that stimulates adenylate cyclase, leading to increased intracellular cAMP level.

P-Glycoprotein: A 170-kDa integral plasma membrane glycoprotein that functions as an adenosine triphosphate-dependent efflux pump, causing multidrug resistance.

Pheochromocytoma: Hormone-producing (mostly catecholamine) neoplasm of the adrenal medulla.

References

1. Sugo, S., Minamino, N., Kangawa, K., Miyamoto, K., Kitamura, K., Sakata, J., Eto, T., and Matsuo, H. (1994). Endothelial cells actively synthesize and secrete adrenomedullin. Biochem. Biophys. Res. Commun. 201, 1160-1166.

2. Ladoux, A., and Frelin, C. (2000). Coordinated Up-regulation by hypoxia of adrenomedullin and one of its putative receptors (RDC-1) in cells of the rat blood-brain barrier. J. Biol. Chem. 275, 39914-39919.

3. Kis, B., Kaiya, H., Nishi, R., Deli, M. A., Abraham, C. S., Yanagita, T., Isse, T., Gotoh, S., Kobayashi, H., Wada, A., Niwa, M., Kangawa, K., Greenwood, J., Yamashita, H., and Ueta Y. (2002). Cerebral endothelial cells are a major source of adrenomedullin. J. Neuroendocrinology 14, 283-293.

4. Kobayashi, H., Minami, S., Yamamoto, R., Masumoto, K., Yanagita, T., Uezono, Y., Tsuchiya, K., Mohri, M., Kitamura, K., Eto, T., and Wada, A. (2000). Adrenomedullin receptors in rat cerebral microvessels. Brain. Res. Mol. Brain. Res. 81, 1-6.

5. Oliver, K. R., Wainwright, A., Edvinsson, L., Pickard, J. D., and Hill, R. G. (2002). Immunohistochemical localization of calcitonin receptorlike receptor and receptor activity-modifying proteins in the human cerebral vasculature. J. Cereb. Blood. Flow. Metab. 22, 620-629.

6. Kis, B., Deli, M. A., Kobayashi, H., Abraham, C. S., Yanagita, T., Kaiya, H., Isse, T., Nishi, R., Gotoh, S., Kangawa, K., Wada, A., Greenwood, J., Niwa, M., Yamashita, H., and Ueta Y. (2001). Adrenomedullin regulates blood-brain barrier functions in vitro. Neuroreport 12, 4139-4142.

7. Michibata, H., Mukoyama, M., Tanaka, I., Suga, S., Nakagawa, M., Ishibashi, R., Goto, M., Akaji, K., Fujiwara, Y., Kiso, Y., and Nakao, K. (1998). Autocrine/paracrine role of adrenomedullin in cultured endothelial and mesangial cells. Kidney Int. 53, 979-985.

Further Reading

Caron, K. M., and Smithies, O. (2002). Multiple roles of adrenomedullin revealed by animal models. Microsc. Res. Tech. 57, 55-59. A review of the adrenomedullin transgenic animal models.

de Boer, A. G., van der Sandt, I. C. J., and Gaillard, P. J. (2003). The role of drug transporters at the blood-brain barrier. Annu. Rev. Pharmacol. Toxicol. 43, 629-656.

Hinson, J. P., Kapas, S., and Smith, D. M. (2000). Adrenomedullin, a multifunctional regulatory peptide. Endocr. Rev. 21, 138-167. The best available detailed review of adrenomedullin research.

Hippenstiel, S., Witzenrath, M., Schmeck, B., Hocke, A., Krisp, M., Krull, M., Seybold, J., Seeger, W., Rascher, W., Schutte, H., and Suttorp N. (2002). Adrenomedullin reduces endothelial hyperpermeability. Circ. Res. 91, 618-625. This paper demonstrates a role for adrenomedullin in the regulation of permeability of peripheral endothelial cells.

Rubin, L. L., and Staddon, J. M. (1999). The cell biology of the blood-brain barrier. Annu. Rev. Neurosci. 22, 11-28.

Capsule Biography

Bela Kis earned his M.D. in 1994 and his Ph.D. in 1998 at Albert Szent-Gyorgyi Medical University, Szeged, Hungary. He spent 2 years as postdoctoral research fellow at the University of Occupational and Environmental Health, Kitakyushu, Japan, where most of his adrenomedullin-related work was accomplished. Now he is a postdoctoral research fellow at Wake Forest University, Winston-Salem, North Carolina. His research interest is vasoactive mediators and blood-brain barrier function as well as neuronal preconditioning.

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