Ischemic brain injury is one of the most common pathophysiological processes affecting more than 400,000 people per year in the US in the form of stroke. Restoration of blood flow following short periods of ischemia has been shown to benefit the brain, however, experimental and clinical evidence indicates that reperfusion following longer periods of ischemia may worsen brain injury. While the effects of ischemia and reperfusion have been extensively studied in neuronal injury, little information regarding these effects on cerebral arteries, and how this dysfunction affects stroke outcome, is available. This study investigates the ischemic and reperfusion effects on cerebral artery function, focusing on myogenic tone and reactivity to pressure, both important components of vascular resistance and autoregulation of cerebral blood flow. The intraluminal suture model of focal cerebral ischemia in rats will be used to induce controlled ischemia and reperfusion in middle cerebral arteries. The arteries will then be dissected from the occluded side of the brain and studied in vitro in a system that allows control of intravascular pressure and continuous measurement of lumen diameter. Arteries will be studied under variable periods of ischemia and reperfusion to determine the threshold duration of ischemia and reperfusion that arteries can still maintain viable myogenic responses (Aim 1). Since preliminary experiments determined that 2 hours of ischemia followed by 24 hours of reperfusion results in significantly diminished reactivity to pressure and abnormal basal tone of middle cerebral arteries, we will investigate alterations in cerebral artery structure (e.g., actin cytoskeleton) and function (e.g., myogenic behavior) that may contribute to the loss of function. In addition, inhibitors of compounds known to be detrimental during ischemia and reperfusion (e.g., nitric oxide, superoxide radical) will be used to determine if cerebral artery function can be preserved during reperfusion (Aim 2). Lastly, one promising therapeutic approach involves thrombolysis to restore blood flow to ischemic regions of the brain; however, the use of thrombolytic agents carries the risk of edema formation and hemorrhage. One mechanism that may contribute to these processes during thrombolysis is an effect of the agents themselves on cerebral artery myogenic behavior. Normal cerebrovascular resistance is important during reperfusion and during treatment with thrombolytic agents if vascular integrity is to be maintained and tissue damage minimized. Therefore, Aim 3 will investigate the effects of two types of thrombolytic agents (tissue-type and urokinase) on cerebral artery function, including myogenic processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040071-05
Application #
6639652
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Jacobs, Tom P
Project Start
1999-07-15
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2005-03-31
Support Year
5
Fiscal Year
2003
Total Cost
$243,057
Indirect Cost
Name
University of Vermont & St Agric College
Department
Neurology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Cipolla, Marilyn J; Godfrey, Julie A; Wiegman, Marchien J (2009) The effect of ovariectomy and estrogen on penetrating brain arterioles and blood-brain barrier permeability. Microcirculation 16:685-93
Cipolla, Marilyn J; Bullinger, Lisa V (2008) Reactivity of brain parenchymal arterioles after ischemia and reperfusion. Microcirculation 15:495-501
Maneen, Matthew J; Cipolla, Marilyn J (2007) Peroxynitrite diminishes myogenic tone in cerebral arteries: role of nitrotyrosine and F-actin. Am J Physiol Heart Circ Physiol 292:H1042-50
Maneen, Matthew J; Hannah, Rachael; Vitullo, Lisa et al. (2006) Peroxynitrite diminishes myogenic activity and is associated with decreased vascular smooth muscle F-actin in rat posterior cerebral arteries. Stroke 37:894-9
Goodrow, Gwen J; Vitullo, Lisa; Cipolla, Marilyn J (2005) Effect of estrogen therapy on cerebral arteries during stroke in female rats. Menopause 12:99-109
Coulson, Rebecca J; Cipolla, Marilyn J; Vitullo, Lisa et al. (2004) Mechanical properties of rat middle cerebral arteries with and without myogenic tone. J Biomech Eng 126:76-81
Cipolla, Marilyn J; Crete, Ryan; Vitullo, Lisa et al. (2004) Transcellular transport as a mechanism of blood-brain barrier disruption during stroke. Front Biosci 9:777-85
Cipolla, Marilyn J; Vitullo, Lisa; McKinnon, John (2004) Cerebral artery reactivity changes during pregnancy and the postpartum period: a role in eclampsia? Am J Physiol Heart Circ Physiol 286:H2127-32
Cipolla, Marilyn J; Li, Rui; Vitullo, Lisa (2004) Perivascular innervation of penetrating brain parenchymal arterioles. J Cardiovasc Pharmacol 44:1-8
Coulson, Rebecca J; Chesler, Naomi C; Vitullo, Lisa et al. (2002) Effects of ischemia and myogenic activity on active and passive mechanical properties of rat cerebral arteries. Am J Physiol Heart Circ Physiol 283:H2268-75

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