Vasogenic edema is the most common form of brain edema observed in clinical practice. It is characterized by an increased permeability of brain capillary endo-thelial cells to macromolecules and by an increased extracellular space and brain water. Although the causes of vasogenic edema following brain ischemia and injury appear to be multifactorial, the basic mechanism of this type of edema is dependent upon alterations in the structural and functional integrity of brain endothelial cells. We postulated that oxygen radicals, superoxide radicals in particular and nitric oxide are involved in the perturbation of the structural and functional integrity of the endothelial cells. We now propose to test this hypothesis using both in vivo mouse models of focal cerebral ischemia, temporary focal cerebral ischemia and reperfusion in transgenic mice overexpressing human CuZn-superoxide dismutase and in non-transgenic CD-1 mice and in vitro cerebral capillary endothelial cells cultures.
Our specific aims are: (1) To investigate the CuZn-SOD dose-dependent effects on vasogenic edema and blood brain barrier permeability change in focal cerebral ischemia in transgenic mice. (2) To elucidate the role of oxidative stress on the developement of vasogenic edema and infarction in a newly established mouse model of temporary focal cerebral ischemia and reperfusion. (3) To elucidate the role of nitric oxide synthase (NOS) and nitric oxide (NO.) on oxidative stress-dependent vasogenic edema and tissue infarction following cerebral ischemia. Will NO. and 02.- act synergistically or independently in promoting vasogenic edema and tissue infarction in cerebral ischemia? (4) To investigate the temporal pattern of heat shock protein (HSP 72) expression and hsp 72 mRNA level in the mouse brain following focal cerebral ischemia. Does the induction and expression of HSP 72 in endothelial cells correlate closely with the development of vasogenic edema following focal cerebral ischemia? (5) To study the role of superoxide radicals and nitric oxide on glutamate- and hypoxia-induced injury and degeneration in primary culture of cerebral endothelial cells of SOD-1 transgenic mice and of normal diploid littermates. These studies have therapeutic implications and will further shed light into molecular and biochemical mechanisms underlying the pathogenesis of vasogenic edema following ischemia and reperfusion.
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