Endothelin-1 Overexpression Leads to Further Water Accumulation and Brain Edema after Middle Cerebral Artery Occlusion via Aquaporin 4 Expression in Astrocytic End-Feet

Abstract

Stroke patients have increased levels of endothelin-1 (ET-1), a strong vasoconstrictor, in their plasma or cerebrospinal fluid. Previously, we showed high level of ET-1 mRNA expression in astrocytes after hypoxia/ischemia. It is unclear whether the contribution of ET-1 induction in astrocytes is protective or destructive in cerebral ischemia. Here, we generated a transgenic mouse model that overexpress ET-1 in astrocytes (GET-1) using the glial fibrillary acidic protein promoter to examine the role of astrocytic ET-1 in ischemic stroke by challenging these mice with transient middle cerebral artery occlusion (MCAO). Under normal condition, GET-1 mice showed no abnormality in brain morphology, cerebrovasculature, absolute cerebral blood flow, blood-brain barrier (BBB) integrity, and mean arterial blood pressure. Yet, GET-1 mice subjected to transient MCAO showed more severe neurologic deficits and increased infarct, which were partially normalized by administration of ABT-627 (ET A antagonist) 5 mins after MCAO. In addition, GET-1 brains exhibited more Evans blue extravasation and showed decreased endothelial occludin expression after MCAO, correlating with higher brain water content and increased cerebral edema. Aquaporin 4 expression was also more pronounced in astrocytic end-feet on blood vessels in GET-1 ipsilateral brains. Our current data suggest that astrocytic ET-1 has deleterious effects on water homeostasis, cerebral edema and BBB integrity, which contribute to more severe ischemic brain injury.

Perinecrotic Hypoxia Contributes to Ischemia/Reperfusion-Accelerated Outgrowth of Colorectal Micrometastases

“…In the past, several compounds that aim at restoring the endothelin-1/nitric oxide imbalance have been successfully applied to reduce microcirculatory disturbances and liver tissue damage. 18,19,54,70,71 Atrasentan is effective in reducing postischemic microcirculatory disturbances in models of renal, 72 cardiac, 73 and cerebral 74 I/R and we here show that, in combination with the nitric oxide donor L-arginine, it provides maximal improvement of the microcirculation after hepatic I/R. Second, agents that target the HIF-1␣ pathway, including 17-DMAG, are gaining increased attention as novel anticancer drugs.…”

Acute and chronic changes in aquaporin 4 expression after spinal cord injury

“…However, it is unknown what upstream signaling may lead to AQP4 expression changes in astrocytes after CNS injury. It has been reported that exposing the brain to hypo-osmotic shock increases AQP4 protein levels (Vajda et al, 2000), and that endothelin-1, which increases after stroke, induces AQP4 expression and edema (Lo et al, 2005). Zhao et al (2005) shows that sulforaphane, an antioxidant gene activator, can also stimulate AQP4 induction, which suggests that AQP4 expression may react to oxidative stress conditions in injured CNS.…”

“…Several groups have reported changes in AQP4 expression after brain injury, or in brain tumors (Vajda et al, 2000;Lo et al, 2005;Zhao et al, 2005;Saadoun et al, 2002). Brain injury, depending on the type, can induce up-or down-regulation of AQP4.…”

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

“…ET-1 receptors (A and B) are widely expressed in the endothelial cells of the cerebral microvasculature as well as in populations of neurons, astrocytes and microglia, and ET-1 is thought to mediate interactions between astrocytes and the cerebral microvasculature (31,32) that have an important role in ischemia or stroke-induced brain edema and injury (31). Ischemia induces upregulation of expression of ET-1/3 and its receptors-A/B in the rat cortex (33), and activation of ET-1 by ischemia induces brain edema via AQP4 in rat astrocytic end-feet (34). In the present study, hypobaric hypoxia-activated cortical ET-1 is also involved in cerebral edema and apoptosis through activation of both CRFR1 and NF-κB, suggesting that antagonists for CRFR1 and ET-1R might be appropriate for treating hypoxia-induced disorders.…”