Vasogenic edema is the most common form of brain edema observed in clinical practice. It is characterized by increased permeability of brain capillary endothelial cells to macromolecules and by increased extracellular space and brain water. Although the causes of vasogenic edema after brain ischemia and injury appear to be multifactorial, the basic mechanisms are dependent on alterations in the structural and functional integrity of brain endothelial cells. We have postulated that oxygen radicals, superoxide radicals in particular, are involved in the perturbation of the structural and functional integrity of endothelial cells. We have demonstrated that cerebral edema and infarction induced by cold injury brain trauma, mitochondrial toxin or focal cerebral ischemia and reperfusion are significantly reduced in transgenic mice that overexpress human CuZn-superoxide dismutase (SOD1) activity, whereas vasogenic edema and infarction are exacerbated in mice that are deficient in SOD1 or mitochondrial SOD (SOD2) activity. We have also demonstrated that overexpression of SOD1 in mice could reduce the intrinsic mitochondrial signaling pathways in brain cells, whereas the endogenous survival signaling is upregulated. We propose to continue investigating the role of oxidative stress in the pathogenesis of vasogenic edema using both in vivo mouse models of focal cerebral ischemia and reperfusion, and cold injury, and in vitro cerebral capillary endothelial cell cultures.
Our specific aims are: 1) To elucidate the intrinsic signaling pathways involving mitochondria in endothelial cell death by apoptosis after CNS injuries. 2) To elucidate the role of mitochondrial dysfunction and oxidative stress in endothelial cell death after CNS injuries. 3) To elucidate the endogenous survival signaling pathway in endothelial cell survival after CNS injuries. 4) To study the compartmentalization and compensatory signaling mechanisms between SOD1 and SOD2 on endothelial cell death/survival in CNS injuries. These studies have therapeutic implications and will shed further light on molecular and cellular mechanisms underlying the pathogenesis of vasogenic edema after CNS injuries.
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