Lack of Aquaporin 9 Reduces Brain Angiogenesis and Exaggerates Neuronal Loss in the Hippocampus Following Intracranial Hemorrhage in Mice

Abstract

Intracranial hemorrhage (ICH) is a common subtype of stroke with high morbidity and mortality. However, few clinical therapies that can reduce ICH-induced brain injury and promote the recovery outcome in ICH patients are available to improve the recovery from ICH. Given that aquaporin 9 (AQP9) plays a critical role in brain edema after ischemic stroke and traumatic brain injury and is involved in the regulation of angiogenesis, we examined the role of AQP9 in preventing neuronal loss and in neovascularization in the dorsal hippocampus (DH) after ICH. We found that intra-DH collagenase-induced ICH increased AQP9 protein levels in the hippocampus, which was associated with behavioral deficits in wild-type mice. However, ICH robustly enhanced behavioral deficits in the AQP9-null mice, as compared with the wild-type mice. Furthermore, neovascularization and proliferation of brain microvascular endothelial cells following ICH were severely impaired in the AQP9-null mice, as compared with the wild-type mice. Finally, hippocampal neuronal loss following ICH became severer in the AQP9-null mice, relative to the wild-type mice. Taken together, our findings indicated that AQP9 in the brain may play a compensatory role in response to ICH, promote brain angiogenesis, and prevent subsequent neuronal death, thus preventing the deterioration of neurological outcome of ICH.

RETRACTED: Long Non-coding RNA LINC00320 Inhibits Tumorigenicity of Glioma Cells and Angiogenesis Through Downregulation of NFKB1-Mediated AQP9

“…More importantly, downregulation of AQP9 was observed to exert inhibitory effects on angiogenesis in our hands. Consistent with this finding, loss of AQP9 has been indicated to suppress brain angiogenesis in the hippocampus after intracranial hemorrhage, as observed in a mouse model (Ji et al, 2017). Therefore, we hypothesized that LINC00320 could inhibit the progression of glioma by reducing AQP9, which was confirmed by our experiments in vitro and in vivo.…”

BMAL1 attenuates intracerebral hemorrhage-induced secondary brain injury in rats by regulating the Nrf2 signaling pathway

“…Although the regions of hippocampus and cortex are not in situ hemorrhagic foci, ICH can lead to secondary nerve injury, including neuronal death and apoptosis in the hippocampus and cortex (5,34). In the present study, ICH rats exhibited cognitive decline, and the hippocampus and cortex presented neuronal death and apoptosis-related changes, consistent with previous studies (35,36). The mechanisms of brain injury after ICH include not only the initial mechanical injury induced by the hematoma mass effect, but also subsequent damage called SBI (1).…”

Flurbiprofen axetil attenuates cerebral ischemia/reperfusion injury by reducing inflammation in a rat model of transient global cerebral ischemia/reperfusion

“…Previous studies showed that AQP4 inhibition might provide a new therapeutic option for reducing brain edema. Together with AQP9, it also plays a critical role in the maintenance of water homeostasis, osmotic regulation, and energy metabolism in the brain as well as in brain edema after ischemic stroke [6,7].…”