The overall goal of this program is to define mechanisms that contribute to and protect against vascular disease. The primary focus is on the impact of cardiovascular risk factors on the cerebral circulation. This Program continues to evolve and successfully integrate emerging molecular techniques with more traditional approaches to examine mechanisms that regulate the structure and function of the vessel wall under normal conditions and in models of disease. The program has several well-defined themes: 1) the impact of cardiovascular risk factors on the vasculature, 2) the importance of oxidative stress in models of vascular disease and stroke, and 3) mechanisms of vascular protection. Modern molecular and mechanistic approaches will be used to examine effects of aging, hypertension, and hyperhomocysteinemia on cerebral blood vessels. We will examine novel and interrelated mechanisms, including the role of reactive oxygen species in intracranial hemorrhage during hypertension, as well vascular dysfunction during aging and hyperhomocysteinemia. Molecular and functional studies are proposed to examine the role of superoxide dismutases and peroxisome proliferator activated receptor-gamma in protecting against intracranial hemorrhage during hypertension, and protecting the vasculature during hyperhomocysteinemia and aging. The program has multiple strengths. First, the investigators have an established record of synergistic and highly productive interaction with a commitment to studies of the cerebral circulation. Second, strong new investigators with key expertise have been integrated into the program. Third, the investigators use diverse and state-of-the-art approaches along with sophisticated methodology. For example, some of the animals used express variants in human genes, allowing the study of vascular consequences in 'humanized'mice, a powerful tool combining human genetics with mechanistic vascular studies. Fourth, the investigators are leaders in several areas of study: cerebral circulation, endothelium, nitric oxide, oxidative stress, vascular protection, vascular structure, and studies of the impact of cardiovascular risk factors on cerebral vascular biology. The program consists of three projects supported by an administrative core and a transgenic and knockout animal core. This highly integrated, multidisciplinary approach should continue to facilitate rapid progress and novel insight into mechanisms that impact cerebral blood vessels in pathophysiology. A better understanding of these mechanisms should provide insight into approaches that could delay, or even halt the progression of cerebral vascular disease - a major contributor to stroke and dementia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Wong, May
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University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
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Ketsawatsomkron, Pimonrat; Keen, Henry L; Davis, Deborah R et al. (2016) Protective Role for Tissue Inhibitor of Metalloproteinase-4, a Novel Peroxisome Proliferator-Activated Receptor-? Target Gene, in Smooth Muscle in Deoxycorticosterone Acetate-Salt Hypertension. Hypertension 67:214-22
Dayal, Sanjana; Gu, Sean X; Hutchins, Ryan D et al. (2015) Deficiency of superoxide dismutase impairs protein C activation and enhances susceptibility to experimental thrombosis. Arterioscler Thromb Vasc Biol 35:1798-804
Chrissobolis, Sophocles; Drummond, Grant R; Faraci, Frank M et al. (2014) Chronic aldosterone administration causes Nox2-mediated increases in reactive oxygen species production and endothelial dysfunction in the cerebral circulation. J Hypertens 32:1815-21
Rodionov, Roman N; Jarzebska, Natalia; Weiss, Norbert et al. (2014) AGXT2: a promiscuous aminotransferase. Trends Pharmacol Sci 35:575-82
De Silva, T Michael; Modrick, Mary L; Ketsawatsomkron, Pimonrat et al. (2014) Role of peroxisome proliferator-activated receptor-? in vascular muscle in the cerebral circulation. Hypertension 64:1088-93
Johnson, Andrew W; Kinzenbaw, Dale A; Modrick, Mary L et al. (2013) Small-molecule inhibitors of signal transducer and activator of transcription 3 protect against angiotensin II-induced vascular dysfunction and hypertension. Hypertension 61:437-42
Chu, Yi; Lund, Donald D; Weiss, Robert M et al. (2013) Pioglitazone attenuates valvular calcification induced by hypercholesterolemia. Arterioscler Thromb Vasc Biol 33:523-32
Klykov, Corinne M; Lentz, Steven R (2013) Trends in clinical laboratory homocysteine testing from 1997 to 2010: the impact of evidence on clinical practice at a single institution. Clin Chem Lab Med 51:671-5
Dayal, Sanjana; Wilson, Katina M; Motto, David G et al. (2013) Hydrogen peroxide promotes aging-related platelet hyperactivation and thrombosis. Circulation 127:1308-16
Miller, Jordan D; Chu, Yi; Castaneda, Lauren E et al. (2013) Vascular function during prolonged progression and regression of atherosclerosis in mice. Arterioscler Thromb Vasc Biol 33:459-65

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