Angiotensin II

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It has been known for many years that the renin-angiotensin system contributes importantly to some forms of hypertension. Recent work suggests that activation of this system may contribute to vascular disease under other pathophysiological conditions, including atherosclerosis and diabetes. Angiotensin II has many effects on vascular cells. In aorta, for example, angiotensin II produces oxida-tive stress, activates components of the inflammatory cascade, and produces endothelial dysfunction.

In the cerebral microcirculation, angiotensin II produces superoxide-mediated endothelial dysfunction and impairs local increases in blood flow in response to somatosensory activation. In stroke-prone spontaneously hypertensive rats (SHRSP) that have endothelial dysfunction, local inhibition of angiotensin-converting enzyme restores endothelial function toward normal, suggesting that endogenous angiotensin II may be a mediator of vascular dysfunction. Using transgenic mice that overexpress both human renin and human angiotensinogen, we have provided evidence that the renin-angiotensin system is an important determinant of microvascular "remodeling" during chronic hypertension.

Acknowledgments

Original studies by the authors that are summarized in this review were supported by National Institutes of Health grants HL-38901, NS-24621, HL-62984, HL-14388, and HL-16066, as well as by funds from the VA Medical Center and from the Carver Trust.

Further Reading

Faraci, F. M., and Heistad, D. D. (1998). Regulation of the cerebral circulation: Role of endothelium. Physiol. Rev. 78, 53-97. Iadecola, C., Zhang, F., Niwa, K., Eckman, C., Turner, S. K., Fischer, E., Younkin, S., Borchel, D. R., Hsiao, K. K., and Carlson, G. A. (1999). SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat. Neurosci. 2, 157-161. A fine example of how genetically altered mice can be used as models of human disease and to study mechanisms of vascular dysfunction.

Kamii, H., Kato, I., Kinouchi, H., Chan, P. H., Epstein, C. J., Akabane, A., Okamoto, H., and Yoshimoto, T. (1999). Amelioration of vasospasm after subarachnoid hemorrhage in transgenic mice overexpressing CuZn-superoxide dismutase. Stroke 30, 867-872.

Mayhan, W. G. (2001). Regulation of blood-brain barrier permeability. Microcirculation 8, 89-104.

Nag, S. (2003). The Blood-Brain Barrier. Methods in Molecular Medicine. Totowa, NJ: Humana Press.

Nitta, T., Hata, M., Gotoh, S., Seo, Y., Sasaki, H., Hashimoto, N., Furuse, M., and Tsukita, S. (2003). Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J. Cell. Biol. 161, 653-660. An excellent example of using modern molecular approaches to study mechanisms that control permeability of the BBB.

Rosenblum, W. I. (1998). Areview of vasomotor responses of arterioles on the surface of the mouse brain: The necessary prelude to studies using genetically manipulated mice. Microcirculation 5, 129-138.

biology of the carotid artery and cerebral circulation with a focus on defining mechanisms that produce vascular dysfunction in disease states. He is an Established Investigator of the American Heart Association and has received the Lamport Award from the American Physiological Society. He is Assistant Editor for Stroke, and Associate Editor for Arteriosclerosis, Thrombosis and Vascular Biology, serves on numerous editorial boards, and is the lead investigator on the Cerebral Vascular Biology Program at the University of Iowa.

Dr. Heistad is Zahn Professor in the Departments of Internal Medicine and Pharmacology at the University of Iowa and staff physician at the VA Medical Center. A major focus of Dr. Heistad's laboratory is physiology and pathophysiology of cerebral blood vessels. He has received the Wiggers Award from the American Physiological Society, the Landis Award from the Microcirculatory Society, and the Research Achievement Award from the American Heart Association. He is Editor-in-Chief of Arteriosclerosis, Thrombosis, and Vascular Biology. His work is supported by grants from the NIH and VA.

Capsule Biography

Dr. Faraci is Professor of Internal Medicine and Pharmacology at the University of Iowa College of Medicine. His research deals with the

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