application) Recent evidence suggests that several types of potassium (K+) channels are present in cerebral blood vessels, and that activation of these channels may play a critical role in relaxation. One major goal of this proposal is to examine the role of K+ channels in regulation of cerebral circulation. Studies are proposed to test the hypothesis that Ca++-dependent K+ channels modulate cerebral vasoconstrictor responses to increases in mean arterial pressure and pulse pressure in vivo. The second major goal is to examine the role of K+ channels in mediation of cerebral vasodilator responses to reactive oxygen species. Studies are proposed to examine the hypotheses that K+ channels mediate cerebral vascular responses to reactive oxygen species (especially H2O2), and that bradykinin, arachidonic acid, and acute severe hypertension, which produce vasodilatation of cerebral vessels. The third major goal of these studies is to examine the role of extracellular superoxide dismutase (ECSOD) in cerebral blood vessels. Recent evidence suggests that ECSOD accounts for about half of total SOD activity in blood vessels. The role of ECSOD is poorly defined, in part because a source for obtaining ECSOD is not available. The gene for ECSOD has been cloned into an adenoviral vector, and thus a method is available to produce ECSOD. Novel methods will be used to transfer genes to blood vessels, with perivascular application to intracranial vessels and the carotid artery in vivo. Studies are proposed to measure ECSOD activity in cerebral vessels, and to use adenovirus-mediated gene transfer of ECSOD to the carotid artery and to intracranial vessels. Studies are planned to test the hypothesis that gene transfer of ECSOD to the carotid artery in vitro and in vivo increases activity of ECSOD and preserves endothelial function after oxidative stress. Studies are also proposed to test the hypothesis that, after gene transfer to intracranial vessels, increases in ECSOD activity prevent """"""""breakthrough"""""""" in autoregulation of cerebral blood vessels and protect the blood-brain barrier against disruption during acute severe hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL016066-24
Application #
2027962
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1976-12-01
Project End
2001-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
24
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Grassi, Guido; Heistad, Donald D (2009) Remodelling of small cerebral arteries in human hypertension: structural and functional alterations. J Hypertens 27:709-11
Heistad, D D; Watanabe, Y; Chu, Y (2008) Gene transfer after subarachnoid hemorrhage: a tool and potential therapy. Acta Neurochir Suppl 104:157-9
Chu, Yi; Miller, Jordan D; Heistad, Donald D (2007) Gene therapy for stroke: 2006 overview. Curr Hypertens Rep 9:19-24
Lund, Donald D; Chu, Yi; Brooks, Robert M et al. (2007) Effects of a common human gene variant of extracellular superoxide dismutase on endothelial function after endotoxin in mice. J Physiol 584:583-90
Kitayama, Jiro; Faraci, Frank M; Lentz, Steven R et al. (2007) Cerebral vascular dysfunction during hypercholesterolemia. Stroke 38:2136-41
Weiss, Robert M; Ohashi, Masuo; Miller, Jordan D et al. (2006) Calcific aortic valve stenosis in old hypercholesterolemic mice. Circulation 114:2065-9
Chu, Yi; Piper, Robert; Richardson, Simon et al. (2006) Endocytosis of extracellular superoxide dismutase into endothelial cells: role of the heparin-binding domain. Arterioscler Thromb Vasc Biol 26:1985-90
Heistad, Donald D (2006) Gene therapy for vascular disease. Vascul Pharmacol 45:331-3
Sethi, Sanjeev; Iida, Shinichiro; Sigmund, Curt D et al. (2006) Renal thrombotic microangiopathy in a genetic model of hypertension in mice. Exp Biol Med (Maywood) 231:196-203
Kitayama, Jiro; Yi, Chu; Faraci, Frank M et al. (2006) Modulation of dilator responses of cerebral arterioles by extracellular superoxide dismutase. Stroke 37:2802-6

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