Proposed studies will examine two aspects of endothelium in the cerebral circulation: permeability of the blood-brain barrier (BBB), and modulation of vascular responses. Experiments that I have completed suggest that veins are the primary site of disruption of the BBB during acute hypertension, and disruption of the BBB in veins was associated with, and presumably due to, increases in pial venous pressure. Experiments that are proposed will examined the determinants of disruption in veins. Studies in other vascular beds suggests that pulsatile pressure and flow release prostaglandins and endothelium-derived relaxing factor (EDRF), which may modulate vascular tone. Thus, changes in pulse pressure may modulate endothelium dependent responses of cerebral arterioles. I plan to 1) examine effects of pulse pressure on arterioles, and determine if prostaglandins and EDRF modulate vascular tone during pulsatile pressure, and 2) examine the role of pulse pressure in disruption of the BBB during hypertension. Hypertensive encephalopathy may be related to passive segmental dilation of cerebral arterioles, i.e., """"""""sausage stringing."""""""" In chronically hypertensive rats, we have observed sausage string in cerebral arterioles. Proposed experiments will examine whether 1) sausage string occurs at the onset of, and presumably contributes to, encephalopathy, and 2) focal dilation of cerebral arterioles during encephalopathy increases venous pressure and disrupts the BBB. Chronic hypertension also produces morphological and functional changes in vascular muscle and endothelium. I have conducted the first in vivo experiments which show impaired endothelium-dependent dilatation of cerebral arterioles in hypertensive rats. Impaired endothelium dilatation during chronic hypertension may predispose hypertensive animals to cerebral ischemia, and perhaps, to stroke. I plan to further investigate altered endothelium-dependent responses of cerebral arterioles during chronic hypertension. Mechanisms of disruption of the BBB during pathologic conditions remain unclear. Disruption of the BBB may be related to increases in vesicular transport, separation of tight endothelial junctions, and/or formation of transendothelial cell pores. I plan to use FITC-dextrans as intravital and electron dense tracers to determine mechanisms of disruption of the BBB during acute hypertension and hyperosmolar arabinose. Techniques to examine permeability of isolated vascular segments in vivo have been developed in other vascular beds. These methods allow examination of diffusive and convective components of transport. I plan to develop and use these techniques to quantitate 1) transport of various sized molecules across cerebral vessels, and 2) contribution of albumin to the integrity of the BBB. This will be the first attempt to determine the permeability of microvessels in the cerebral circulation in vivo.
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