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 four 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 the hypothesis that superoxide generation is an important mediator of endothelial dysfunction. We will use chemiluminescence detection in endothelial cells, and dihydroethidium staining in sections and in vivo. We will also test the effects of superoxide scavengers on cerebral vascular reactivity (Aim 1) and effects on ischemia (Aim 2).
Aim 4 tests whether genetic or pharmacologic interventions directed at augmenting endothelial NO production will restore cerebrovascular reactivity (Aim 1), and ameliorate the response to ischemia (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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048426-04
Application #
7210549
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Jacobs, Tom P
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$189,637
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Kashiwagi, Satoshi; Atochin, Dmitriy N; Li, Qian et al. (2013) eNOS phosphorylation on serine 1176 affects insulin sensitivity and adiposity. Biochem Biophys Res Commun 431:284-90
Zhang, Xiuqin; Zhang, Rongli; Raab, Susanne et al. (2011) Rhesus macaques develop metabolic syndrome with reversible vascular dysfunction responsive to pioglitazone. Circulation 124:77-86
Kuhlencordt, Peter J; Padmapriya, P; Rützel, S et al. (2009) Ezetimibe potently reduces vascular inflammation and arteriosclerosis in eNOS-deficient ApoE ko mice. Atherosclerosis 202:48-57
Liu, Victor W T; Huang, Paul L (2008) Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice. Cardiovasc Res 77:19-29
Yamova, Liubov; Atochin, Dmitriy; Glazova, Margarita et al. (2007) Role of neuronal nitric oxide in the regulation of vasopressin expression and release in response to inhibition of catecholamine synthesis and dehydration. Neurosci Lett 426:160-5
Shin, Hwa Kyoung; Salomone, Salvatore; Potts, E Michelle et al. (2007) Rho-kinase inhibition acutely augments blood flow in focal cerebral ischemia via endothelial mechanisms. J Cereb Blood Flow Metab 27:998-1009
Lee, S-R; Lok, J; Rosell, A et al. (2007) Reduction of hippocampal cell death and proteolytic responses in tissue plasminogen activator knockout mice after transient global cerebral ischemia. Neuroscience 150:50-7
Atochin, Dmitriy N; Wang, Annie; Liu, Victor W T et al. (2007) The phosphorylation state of eNOS modulates vascular reactivity and outcome of cerebral ischemia in vivo. J Clin Invest 117:1961-7
Hurt, K Joseph; Sezen, Sena F; Champion, Hunter C et al. (2006) Alternatively spliced neuronal nitric oxide synthase mediates penile erection. Proc Natl Acad Sci U S A 103:3440-3
Kuhlencordt, Peter J; Hotten, Stefanie; Schodel, Johannes et al. (2006) Atheroprotective effects of neuronal nitric oxide synthase in apolipoprotein e knockout mice. Arterioscler Thromb Vasc Biol 26:1539-44

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