Although cerebral ischemia and stroke commonly occur in patients with atherosclerosis, the specific effects of atherosclerotic vascular abnormalities are not reflected in most animal models of stroke. This proposal addresses the effects of atherosclerosis and endothelial dysfunction on cerebrovascular function, reactivity, and response to ischemia, using Western diet-fed apoE knockout mice as an animal model. We have found that apoE knockout mice show decreased resting cerebral blood flow, impaired response to whisker stimulation, and impaired autoregulation, while the response to hypercapnia is relatively preserved. In addition, apoE knockout mice have substantially larger infarcts after middle cerebral artery occlusion than do wild-type mice. We propose three specific aims:
Aim 1 tests the hypothesis that hypercholesterolemia and endothelial dysfunction alter cerebrovascular anatomy, physiology (hypercapnia, whisker stimulation, and autoregulation), and pharmacology (pial arteriolar response in cranial window studies) of apoE knockout mice.
Aim 2 examines the effects of atherosclerosis and endothelial dysfunction on the response to focal ischemia. We will use high-resolution laser speckle imaging to generate real-time maps of temporal and spatial pattern of cerebral blood flow, and quantitate effects on leukocyte-endothelial cell interactions.
Aim 3 tests whether abnormalities in NO generation underlie cerebrovascular abnormalities in apoE knockout mice. We will determine whether genetic or pharmacologic interventions directed at augmenting endothelial NO production will restore cerebrovascular reactivity, and ameliorate the response to ischemia. These studies will establish the link between abnormalites in NO generation, the abnormal responses seen in Aim 1, and the response to ischemia studied in Aim 2. Together, these experiments outline how atherosclerosis and endothelial dysfunction affect the cerebrovasculature, and whether pathophysiologic mechanisms operative in the peripheral circulation also apply to the cerebrovasculature. They also provide proof of principle for approaches that directly target cerebral vascular dysfunction for the treatment and prevention of stroke.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
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

Showing the most recent 10 out of 128 publications