Limited studies indicate an important role of mitochondrial-derived factors in the control of the cerebral circulation beyond effects which are related to energy supply. Thus, factors which depolarize mitochondria and/or augment the release of ROS from mitochondria activate signaling pathways leading to net dilation of cerebral arteries. Furthermore, our preliminary data indicate that mitochondrial influences are adversely affected by insulin resistance (IR). Our overall hypothesis is that mitochondrial-derived influences are key regulators of cerebral vascular tone but are compromised by IR.
Two Specific Aims will test our hypotheses and speculations in rats:
Aim 1. Examination of the roles of mitochondrial-derived influences in mediating responses of cerebral arteries. We will: A) Determine the relationship among cerebral arterial vasodilation, mitochondrial depolarization, kinase activation, and mitochondrial ROS production. B) Elucidate the mechanisms of dilation due to mitochondrial depolarization, kinase activation, ROS generation, and plasmalemmal calcium-activated potassium channel opening. C) Evaluate the inter-relationships of mitochondrial-derived factors produced in endothelium and VSM cells in mediating integrated dilator responses. D) Determine whether preconditioning, induced by prior activation of mitochondrial-derived mechanisms, alters subsequent cerebrovascular responses to mitochondrial-derived products. E) Explore the relationship between physiological stimuli and mitochondrial activation.
Aim 2. Investigation of the effects of IR on mitochondrial-derived influences on cerebral arteries. We will: A) Examine whether IR attenuates dilator responses of cerebral arteries dependent upon mitochondria-derived signaling pathways. B) Determine the mechanisms by which IR reduces the responsiveness of cerebral arteries to mitochondrial-derived influences. C) Examine whether treatment of animals with statins restores normal responsiveness to mitochondrial-derived stimuli in IR. We expect that our results will lead to the improved treatment of patients suffering from cerebrovascular disease.

Public Health Relevance

Chronic cerebral vascular insufficiency, which occurs in IR, leads to neurological diseases such as Alzheimer's disease and strokes. However, the potential role of mitochondrial dysfunction has not been studied. Current treatment regimens are not optimal and we expect that the results of our studies will lead to new and improved therapies to prevent or slow the onset of neurological diseases in an aging population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093554-05
Application #
8447025
Study Section
Special Emphasis Panel (ZRG1-CVS-F (02))
Program Officer
Charette, Marc F
Project Start
2009-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$354,608
Indirect Cost
$118,988
Name
Tulane University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Katakam, Prasad V G; Gordon, Angellica O; Sure, Venkata N L R et al. (2014) Diversity of mitochondria-dependent dilator mechanisms in vascular smooth muscle of cerebral arteries from normal and insulin-resistant rats. Am J Physiol Heart Circ Physiol 307:H493-503
Busija, David W; Katakam, Prasad V (2014) Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning. J Vasc Res 51:175-89
Rutkai, Ibolya; Katakam, Prasad V G; Dutta, Somhrita et al. (2014) Sustained mitochondrial functioning in cerebral arteries after transient ischemic stress in the rat: a potential target for therapies. Am J Physiol Heart Circ Physiol 307:H958-66
Carvalho, Cristina; Katz, Paige S; Dutta, Somhrita et al. (2014) Increased susceptibility to amyloid-? toxicity in rat brain microvascular endothelial cells under hyperglycemic conditions. J Alzheimers Dis 38:75-83
Katakam, Prasad V G; Wappler, Edina A; Katz, Paige S et al. (2013) Depolarization of mitochondria in endothelial cells promotes cerebral artery vasodilation by activation of nitric oxide synthase. Arterioscler Thromb Vasc Biol 33:752-9
Wappler, Edina A; Institoris, Adam; Dutta, Somhrita et al. (2013) Mitochondrial dynamics associated with oxygen-glucose deprivation in rat primary neuronal cultures. PLoS One 8:e63206
Katakam, Prasad V G; Snipes, James A; Steed, Mesia M et al. (2012) Insulin-induced generation of reactive oxygen species and uncoupling of nitric oxide synthase underlie the cerebrovascular insulin resistance in obese rats. J Cereb Blood Flow Metab 32:792-804
Institoris, Adam; Snipes, James A; Katakam, Prasad V et al. (2011) Impaired vascular responses of insulin-resistant rats after mild subarachnoid hemorrhage. Am J Physiol Heart Circ Physiol 300:H2080-7
Domoki, Ferenc; Kis, Bela; Gaspar, Tamas et al. (2010) Rosuvastatin induces delayed preconditioning against L-glutamate excitotoxicity in cultured cortical neurons. Neurochem Int 56:404-9
Lenti, Laura; Domoki, Ferenc; Gaspar, Tamas et al. (2009) N-methyl-D-aspartate induces cortical hyperemia through cortical spreading depression-dependent and -independent mechanisms in rats. Microcirculation 16:629-39

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