Background: Although inflammatory cell adhesion molecules (CAMs) and anti-inflammation factor Kruppel-like transcription factor (KLF) 4 have all been reported to be induced after cerebral ischemic stroke (CIS), the close temporal and spatial relationship between expressions of CAMs and KLF4 following CIS and whether and how CAMs and KLF-4 contribute to the development of CIS-induced vascular injury are still unclear. Methods: Here, we first examined the correlation between serum levels of CAMs/KLF4 and infarct volume in acute CIS patients. Then, we determined the relationship between CAMs and KLF4 in mice after focal cerebral ischemia. Finally, we investigated the mechanism of KLF4 in protecting against oxygen-glucose deprivation-induced brain endothelial cell injury.

The aim of this study was to investigate the function and regulatory mechanism of long non-coding RNA (lncRNA) X-inactive-specific transcript (XIST) in cerebral ischemic stroke (CIS). The impact of lncRNA XIST on CIS was evaluated in acute CIS patients, middle cerebral artery occlusion (MCAO) mice, and oxygen-glucose deprivation and restoration brain endothelial cells. Our results demonstrated that the expression of lncRNA XIST decreased during the early stages of CIS but then increased in the later stages in CIS patients and ischemic models in vivo and in vitro. In addition, the serum levels of lncRNA XIST negatively correlated with severity of neurological impairment of CIS patients. Further studies exhibited that lncRNA XIST regulated the expression of proangiogenic factor-integrin a5 (Itga5) and anti-inflammation factor-Kruppel-like transcription factor 4 (KLF4) by targeting microRNA-92a (miR-92a). Silencing of lncRNA XIST impaired angiogenesis and exacerbated cerebral vascular injury following CIS, leading to larger infarcts and worse neurological deficits in transient MCAO mice. Mechanistic analysis revealed that lncRNA XIST modulated angiogenesis and alleviated cerebral vascular injury following CIS through mediating the miR-92a/Itga5 or KLF4 axis, respectively. These data indicate that lncRNA XIST confers protection against CIS, providing a valuable target for future prevention and treatment of CIS.

We have previously demonstrated that in response to cerebral ischemia (CI), the growth factor angiopoietin-1 (Ang1) and α5β1 integrin are both induced in cerebral vessels, which likely provide positive signals driving the endogenous angiogenic response and vascular protection after CI. However, the precise relationship between endothelial Ang1 and α5β1 integrin after CI remains poorly understood. Here, we investigated the effects of the interaction between the Ang1/Tie2 system and α5β1 integrin on brain endothelial cells (BECs) under cerebral ischemic conditions in vivo and in vitro. Immunofluorescence analysis demonstrated that integrin α5β1 co-localized with Tie2/phosphorylated Tie2 on cerebral vessels in the penumbra. The in vitro study showed that oxygen–glucose deprivation/restoration (OGD/R) induced the expression of the Ang1 receptor Tie2 on BECs in a manner similar to that for integrin α5 and Ang1 in response to OGD/R, accompanied by increased activation of Tie2 and its downstream effectors focal adhesion kinase (FAK) and Akt. Knockdown of α5 integrin markedly suppressed OGD/R-induced Tie2 receptor activation in BECs, while in contrast, priming BECs with Ang1 promoted the expression of α5 integrin as well as the Tie2 downstream transcription factor Ets-1 in OGD-treated BECs. In line with this, Ets-1 knockdown significantly attenuated Ang1-mediated upregulation of α5 integrin. Functionally, Ang1 induced cell migration and tube formation of BECs after OGD, but this effect was inhibited by diminishment of the levels of α5 integrin in BECs. Taken together, our data indicate that the Ang1/Tie2 system cross-talks with integrin α5β1 in BECs after CI, which may contribute to the endogenous angiogenic vascular protective response following CI.