The purpose of this project is to define hemostatic regulatory mechanisms of the brain. Because thrombo-occlusive processes are so important for stroke pathophysiology, brain regulation of hemostasis is a critical issue. Our work has been the first to show the hemostatic regulatory capacity of the blood-brain barrier, a function that we have termed """"""""brain- specific hemostasis"""""""". We propose to further analyze this phenomenon by studying pericyte-endothelial and pericyte- astrocyte-endothelial interactions in blood-brain barrier models using human cells. These cells will be grown a) as monolayers; and b) in an artificial capillary network. We will continue to delineate the role of transforming growth factor-beta (TGF-beta) as a critical mediator of brain-specific hemostasis. We will also define the unique anticoagulant system within the brain that compensates for paucity of antithrombotic factors (eg, thrombomodulin) prevalent in the systemic vasculature. Candidates for endothelial antithrombotic molecules upregulated by astrocytes and pericytes include tissue factor pathway inhibitor, the protease nexins, prostacylin, and endothelial nitric oxide. Finally, we will analyze the role of shear stress on brain-specific hemostasis by subjecting a capillary network of endothelial cells, astrocytes, and pericytes to physiological and low shear stresses. Our findings will define pathways of brain regulation of hemostasis, add to the emerging field of vascular bed-specific hemostasis regulation, and pave the way for strategies to prevent and treat stroke by modulation of the brain's endogenous anticoagulant system.
| Fisher, Mark; Kapur, Kevin; Soo, Sylvia et al. (2018) Disseminated Microinfarctions with Cerebral Microbleeds. J Stroke Cerebrovasc Dis 27:e95-e97 |
| Sumbria, Rachita K; Grigoryan, Mher Mahoney; Vasilevko, Vitaly et al. (2018) Aging exacerbates development of cerebral microbleeds in a mouse model. J Neuroinflammation 15:69 |
| Chang, Rudy; Castillo, Juan; Zambon, Alexander C et al. (2018) Brain Endothelial Erythrophagocytosis and Hemoglobin Transmigration Across Brain Endothelium: Implications for Pathogenesis of Cerebral Microbleeds. Front Cell Neurosci 12:279 |
| Sumbria, Rachita K; Vasilevko, Vitaly; Grigoryan, Mher Mahoney et al. (2017) Effects of phosphodiesterase 3A modulation on murine cerebral microhemorrhages. J Neuroinflammation 14:114 |
| Hainsworth, Atticus H; Fisher, Mark J (2017) A dysfunctional blood-brain barrier and cerebral small vessel disease. Neurology 88:420-421 |
| Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly et al. (2016) Corrigendum to ""Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy"" [105, May 2016, 109-113]. Microvasc Res 106:137 |
| Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly et al. (2016) Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy. Microvasc Res 105:109-13 |
| Passos, Giselle F; Kilday, Kelley; Gillen, Daniel L et al. (2016) Experimental hypertension increases spontaneous intracerebral hemorrhages in a mouse model of cerebral amyloidosis. J Cereb Blood Flow Metab 36:399-404 |
| Sumbria, Rachita K; Grigoryan, Mher Mahoney; Vasilevko, Vitaly et al. (2016) A murine model of inflammation-induced cerebral microbleeds. J Neuroinflammation 13:218 |
| Fisher, Mark; Moores, Lisa; Alsharif, Mohamad N et al. (2016) Definition and Implications of the Preventable Stroke. JAMA Neurol 73:186-9 |
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