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    • Cerebral ischemia occurs following the occlusion of a

    2024-03-22

    Cerebral ischemia occurs following the occlusion of a cerebral artery by a thrombus and causes cell swelling due to cytotoxic edema and BBB disruption with vasogenic edema (Loreto and Reggio, 2010, Nakaji et al., 2006, Shibata et al., 2004). Vasogenic edema is directly linked to alteration of the BBB tight junctions with increasing permeability to many molecules (Ayata and Ropper, 2002, Heo et al., 2005). Several studies have demonstrated that edema is an important reason underlying clinical deterioration following ischemia and reperfusion (I/R) (Bounds et al., 1981, Davalos et al., 1999). The activation of ASK1 is regulated by the cellular redox state (Saitoh et al., 1998) and is associated with oxidative stress–induced BBB disruption (Toyama et al., 2014). In the present study, we suggested the role of ASK1 on vascular permeability and edema formation both in ischemia injured Quinupristin-Dalfopristin Complex mesylate and in cultured brain endothelial cells under ischemia-induced oxidative stress. VEGF has been reported to exert protective effects on neurons (Mackenzie and Ruhrberg, 2012) and can enhance postischemic neurogenesis in brain (Sun et al., 2003, Wang et al., 2007, Wang et al., 2009). VEGF binds to its receptor (VEGFR) on endothelial cells and promotes many downstream signaling cascades, thus inducing vessel permeability and endothelial cell proliferation and migration (Gille et al., 2001, Keck et al., 1989, Waltenberger et al., 1994). Several studies have demonstrated that VEGF increases BBB permeability by stimulating the release of nitric oxide (Mayhan, 1999), and VEGF is involved in the degradation of the tight junction protein claudin-5, which contributes to a specific mechanism in BBB breakdown (Argaw et al., 2009). In addition, activation of the HIF-1α-VEGF pathway mediates the phosphorylation of tight junction proteins in response to hypoxic stress (Engelhardt et al., 2014). VEGF has been reported to reduce infarct size (Bellomo et al., 2003, Stowe et al., 2007, Stowe et al., 2008, Wang et al., 2005) and brain edema (Harrigan et al., 2002, Kimura et al., 2005, van Bruggen et al., 1999, Zhang et al., 2000) after cerebral ischemia. In transient MCAO mice, the relationship between VEGF and brain edema was shown in experiments with VEGFR-1 fusion protein (van Bruggen et al., 1999). Intravenous administration of VEGF to rats 1h after MCAO was also demonstrated to reduce brain infarct size (Zhang et al., 2000). VEGF also induces the phosphorylation of ASK1 and c-Jun, which are related to JNK/SAPK signaling (Shen et al., 2012). A recent study suggested that oxidative stress-stimulated ASK1 activation leads to endothelial apoptosis, and VEGF suppresses endothelial apoptosis by inhibiting ASK1 activation (Nako et al., 2012). In the present study, we focused on the relationship between ASK1 and VEGF in hypoxia-induced brain endothelial cells and MCAO mouse brain to clarify the role of ASK1 in vascular permeability and edema formation. Our results suggest that ASK1 is associated with VEGF expression in brain endothelial cells at reperfusion early time point after hypoxia injury, and aggravates vascular permeability, and finally stimulates edema formation. Based on our results, ASK1 fast was activated in response to reperfusion condition after hypoxia injury and subsequently may stimulate vascular permeability in brain endothelial cells by modulating the expression of VEGF. AQP-1 is involved in brain water homeostasis (Arcienega et al., 2010) and is expressed in the apical membrane of the choroid plexus epithelium and in the lining of the cerebral ventricles (Oshio et al., 2005), where it plays an important role in cerebrospinal fluid (CSF) formation (Longatti et al., 2004, Nielsen et al., 1993). Recent studies have demonstrated that AQP-1 deletion in mice decreases the osmotic water permeability of the choroid plexus and lowers CSF production (Oshio et al., 2003, Oshio et al., 2005). Several studies have suggested that downregulation of AQP1 expression in the choroid plexus reduces brain edema formation (Kim et al., 2007), whereas its upregulation in endothelial cells leads to increased water permeability of the capillary walls and greater water entry to the brain (McCoy and Sontheimer, 2007). Others reported that AQP-1 expression changes in the ischemic stroke brain and is associated with edema formation (Badaut et al., 2007, Ribeiro Mde et al., 2006). In the present study, we found that ASK1 accelerated the activation of AQP-1 in the MCAO mouse brain. Considering our results, we suggest that the inhibition of ASK1 may attenuate increased osmotic water permeability following cerebral ischemia by inhibiting the activation of AQP-1 in ischemic brain. Taken together, our findings suggest that ASK1 may be activated at reperfusion early time point in cerebral ischemia and subsequently may be involved in the increase of VEGF and AQP-1 expression, ultimately resulting in edema formation. Thus, we conclude that the inhibition of ASK1 activation might be a target to treat clinical pathologies that occur after ischemic stroke.