Ischemic stroke is one of the most common pathophysiologic events affecting more than 750,000 people per year in the US. Preexisting hyperglycemia, present in ~20% of all stroke patients, is associated with enhanced reperfusion injury in the postischemic brain, including a significantly higher incidence and severity of cerebral infarction and edema formation. While most studies have focused on metabolic derangements or neuronal tissue damage during hyperglycemic stroke, our preliminary data demonstrate that there is a direct effect of glucose on the vasculature that leads to poor perfusion and increased vascular damage during ischemia and reperfusion (I/R). Our preliminary data also demonstrate that hyperglycemia upregulates signaling molecules within the vascular wall, including protein kinase C (PKC) and reactive oxygen species (ROS) that we have hypothesized has an effect on vascular function (tone, permeability) to decrease reperfusion and enhance vasogenic edema during I/R. In addition, augmented ischemia created during hyperglycemic stroke leads to enhanced reperfusion injury that further damages the vasculature. This proposal is focused on understanding 1) how elevated glucose prior to stroke affects cerebrovascular function in a way that influences postischemic reperfusion and stroke outcome, and 2) how hyperglycemia, in combination with I/R, augments vascular damage. The middle cerebral artery occlusion model in rats will be used under normoglycemic and hyperglycemic conditions to induce controlled I/R, after which penetrating brain parenchymal arterioles will be dissected from the brain tissue and studied in vitro in a pressurized arteriograph system that allows for control over intravascular pressure, measurement of lumen diameter, and perfusion with fluorescent and electron dense tracers for determination of permeability.
Aim 1 of this proposal will investigate the role of glucose-induced PKC activation and ROS production in mediating changes in arteriole function prior to stroke and how those changes influence stroke outcome.
Aim 2 will determine how hyperglycemia during stroke affects vascular integrity, including vascular smooth muscle and endothelial cell damage. The proposed studies are the first to specifically investigate the direct effect of I/R and hyperglycemia on small penetrating brain arterioles that are in close association with other cell types in the brain, including astrocytes, pericytes and neurons that are known to have significant interaction with the vasculature and can influence perfusion, permeability, and stroke outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043316-04
Application #
7415004
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (90))
Program Officer
Jacobs, Tom P
Project Start
2005-07-15
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$299,957
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
Palomares, Sara Morales; Sweet, Julie G; Cipolla, Marilyn J (2012) Acute rosiglitazone treatment during reperfusion after hyperglycemic stroke is neuroprotective not vascular protective. Transl Stroke Res 3:390-6
Palomares, Sara Morales; Gardner-Morse, Ira; Sweet, Julie G et al. (2012) Peroxynitrite decomposition with FeTMPyP improves plasma-induced vascular dysfunction and infarction during mild but not severe hyperglycemic stroke. J Cereb Blood Flow Metab 32:1035-45
Mandala, M; Pedatella, A L; Morales Palomares, S et al. (2012) Maturation is associated with changes in rat cerebral artery structure, biomechanical properties and tone. Acta Physiol (Oxf) 205:363-71
Palomares, Sara Morales; Cipolla, Marilyn J (2011) Vascular Protection Following Cerebral Ischemia and Reperfusion. J Neurol Neurophysiol 2011:
Cipolla, Marilyn J; Huang, Quillan; Sweet, Julie G (2011) Inhibition of protein kinase C? reverses increased blood-brain barrier permeability during hyperglycemic stroke and prevents edema formation in vivo. Stroke 42:3252-7
Cipolla, Marilyn J; Bishop, Nicole; Vinke, R Saman et al. (2010) PPAR{gamma} activation prevents hypertensive remodeling of cerebral arteries and improves vascular function in female rats. Stroke 41:1266-70
Cipolla, Marilyn J; Godfrey, Julie A (2010) Effect of hyperglycemia on brain penetrating arterioles and cerebral blood flow before and after ischemia/reperfusion. Transl Stroke Res 1:127-34
Roberts, Tim J M; Chapman, Abbie C; Cipolla, Marilyn J (2009) PPAR-gamma agonist rosiglitazone reverses increased cerebral venous hydraulic conductivity during hypertension. Am J Physiol Heart Circ Physiol 297:H1347-53
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; Smith, Jeremiah; Kohlmeyer, Meghan M et al. (2009) SKCa and IKCa Channels, myogenic tone, and vasodilator responses in middle cerebral arteries and parenchymal arterioles: effect of ischemia and reperfusion. Stroke 40:1451-7

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