This proposal examines the role of nitric oxide (NO) as a mediator of the cellular and molecular events which promote dilation in the cerebrovasculature. NO is formed within vessels and brain parenchyma by the enzyme NOS (nitric oxide synthase), and both are potential mediators of vasodilation. NO synthesis involves the incorporation of molecular oxygen and L-arginine [L-ARG] into NO and citrulline. Linkage between NO, dilation and rCBF increases during hypercapnia, and brain metabolism has been established by L-arginine substrate analogues that inhibit NOS. We propose to use mutant mice in which either vascular (KV) or neuronal (KN isoforms of NOS have been selectively knocked-out to determine the role of NO in normal rCBF regulation and during ischemia. To these ends, we have: established a dedicated mouse physiology unit (2 stations) in which rCBF, expiratory CO2, arterial blood pressure, core and brain temperature, EcoG can be monitored on-line from mechanically ventilated animals and developed in the mouse, the thread model of focal ischemia. The goals of these experiments are to:
(AIM I) characterize the responses of pial vessels to topical endothelium-dependent relaxing factor (EDRF) and non-EDRF generating compounds in Wild type and mutants, (Aim II) determine the role and sources of NO during hypercapnia and cortical barrel field activation.
(Aim III) examine the role of NO in focal and global cerebral ischemia. We will compare and contrast the evolution of infarction in the Wild type to KV and KN following middle cerebral artery occlusion (MCAO) (thread models) and ischemia reperfusion [bilateral CCA (common carotid artery) + hypotension] and determine whether the lack of neuronal and/or vascular NOS affects the volume of tissue injury, the production of free radicals, the extent of cellular injury as compared to Wild type, and the adaptive circulatory responses which characterize focal and global ischemia. By so doing, we hope to clarify whether vascular and/or neuronal NO mechanisms predominate in response to focal ischemia and to thereby clarify the molecular events underlying the regulation of the cerebrovasculature during health and disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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Massachusetts General Hospital
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Yaseen, Mohammad A; Srinivasan, Vivek J; Gorczynska, Iwona et al. (2015) Multimodal optical imaging system for in vivo investigation of cerebral oxygen delivery and energy metabolism. Biomed Opt Express 6:4994-5007
Miao, Yanying; Liao, James K (2014) Potential serum biomarkers in the pathophysiological processes of stroke. Expert Rev Neurother 14:173-85
Sawada, Naoki; Liao, James K (2014) Rho/Rho-associated coiled-coil forming kinase pathway as therapeutic targets for statins in atherosclerosis. Antioxid Redox Signal 20:1251-67
Tanaka, Shin-ichi; Fukumoto, Yoshihiro; Nochioka, Kotaro et al. (2013) Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation. Arterioscler Thromb Vasc Biol 33:1591-600
Montalvo, J; Spencer, C; Hackathorn, A et al. (2013) ROCK1 & 2 perform overlapping and unique roles in angiogenesis and angiosarcoma tumor progression. Curr Mol Med 13:205-19
Yaseen, Mohammad A; Sakadži?, Sava; Wu, Weicheng et al. (2013) In vivo imaging of cerebral energy metabolism with two-photon fluorescence lifetime microscopy of NADH. Biomed Opt Express 4:307-21
Hayakawa, Kazuhide; Miyamoto, Nobukazu; Seo, Ji Hae et al. (2013) High-mobility group box 1 from reactive astrocytes enhances the accumulation of endothelial progenitor cells in damaged white matter. J Neurochem 125:273-80
Zhou, Qian; Mei, Yu; Shoji, Takuhito et al. (2012) Rho-associated coiled-coil-containing kinase 2 deficiency in bone marrow-derived cells leads to increased cholesterol efflux and decreased atherosclerosis. Circulation 126:2236-47
Sakadži?, Sava; Roussakis, Emmanuel; Yaseen, Mohammad A et al. (2011) Cerebral blood oxygenation measurement based on oxygen-dependent quenching of phosphorescence. J Vis Exp :
Yaseen, Mohammad A; Srinivasan, Vivek J; Sakadzic, Sava et al. (2011) Microvascular oxygen tension and flow measurements in rodent cerebral cortex during baseline conditions and functional activation. J Cereb Blood Flow Metab 31:1051-63

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