Endothelium (EC) is a key component of blood–brain barrier (BBB), and has an important position in the neurovascular unit. Its dysfunction and death after cerebral ischemic/reperfusion (I/R) injury not only promote evolution of neuroinflammation and brain edema, but also increase the risk of intracerebral hemorrhage of thrombolytic therapies. However, the mechanism and specific interventions of EC death after I/R injury are poorly understood. Here we showed that necroptosis was a mechanism underlying EC death, which promoted BBB breakdown after I/R injury. Treatment of rats with receptor interacting protein kinase 1 (RIPK1)-inhibitor, necrostatin-1 reduced endothelial necroptosis and BBB leakage. We furthermore showed that perivascular M1-like microglia-induced endothelial necroptosis leading to BBB disruption requires tumor necrosis factor-α (TNF-α) secreted by M1 type microglia and its receptor, TNF receptor 1 (TNFR1), on endothelium as the primary mediators of these effects. More importantly, anti-TNFα (infliximab, a potent clinically used drug) treatment significantly ameliorate endothelial necroptosis, BBB destruction and improve stroke outcomes. Our data identify a previously unexplored role for endothelial necroptosis in BBB disruption and suggest infliximab might serve as a potential drug for stroke therapy.

Micromotors are important for a wide variety of applications. Here, we develop a microfluidic approach for one-step fabrication of a Janus self-propelled micromotor with multiple functions. By fine tuning the fabrication parameters and loading functional nanoparticles, our micromotor reaches a high speed and achieves an oriented function to promote the water purification efficiency and recycling process.

Diabetic retinopathy (DR) is a common complication of diabetes and leads to blindness. Anti-VEGF is a primary treatment for DR. Its therapeutic effect is limited in non-or poor responders despite frequent injections. By performing a comprehensive analysis of the semaphorins family, we identified the increased expression of Sema4D during oxygen-induced retinopathy (OIR) and streptozotocin (STZ)-induced retinopathy. The levels of soluble Sema4D (sSema4D) were significantly increased in the aqueous fluid of DR patients and correlated negatively with the success of anti-VEGF therapy during clinical follow-up. We found that Sema4D/PlexinB1 induced endothelial cell dysfunction via mDIA1, which was mediated through Src-dependent VE-cadherin dysfunction. Furthermore, genetic disruption of Sema4D/PlexinB1 or intravitreal injection of anti-Sema4D antibody reduced pericyte loss and vascular leakage in STZ model as well as alleviated neovascularization in OIR model. Moreover, anti-Sema4D had a therapeutic advantage over anti-VEGF on pericyte dysfunction. Anti-Sema4D and anti-VEGF also conferred a synergistic therapeutic effect in two DR models. Thus, this study indicates an alternative therapeutic strategy with anti-Sema4D to complement or improve the current treatment of DR.

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Van der Waals heterostructures (vdWHs) have opened new avenues for fundamental scientific studies and design of novel devices. Although numerous reports have demonstrated vdWH optoelectronic devices, no report on vdWH lasers can be found to date. In this paper we demonstrated electrically driven vdWH lasers for the first time, and the lasers were realized from ZnO microwire/MgO/p-GaN structures. By coating Ag films on the top surfaces of the ZnO microwires, the current injection and lasing directionality of the vdWH lasers have been improved significantly, and this improvement can be attributed to the high conductivity and reflectivity of the Ag film. The output power of the device can reach 2.41 μW under 14 mA drive current, which is among the highest values ever reported for ZnO based lasers. Our results may provide a promising way to electrically pumped lasers based on micro/nano-structures.

Angiogenesis is a crucial defense response to hypoxia that regulates the process of raising the promise of long‐term neurologic recovery during the management of stroke. A high expression of antiangiogenic factors leads to the loss of neovascularization capacity in pathologic conditions. We have previously documented an impairment of the cerebral vessel perfusion and neovascularization in the cortex neighboring the stroke‐induced lesion, which was accompanied by an activation of semaphorin 3E (Sema3E)/PlexinD1 after ischemic stroke. In this study, we employed micro‐optical sectioning tomography to fully investigate the details of the vascular pattern, including the capillaries. We found that after transient middle cerebral artery occlusion, inhibiting PlexinD1 signaling led to an organized recovery of the vascular network in the ischemic area. We then further explored the possible mechanisms. In vivo, Sema3E substantially decreased dynamic delta‐like 4 (DLL4) expression. In cultured brain microvascular endothelial cells, Sema3E down‐regulated DLL4 expression via inhibiting Ras‐related C3 botulinum toxin substrate 1–induced JNK phosphorylation. At the microcosmic level, Sema3E/PlexinD1 signaling promoted F‐actin disassembly and focal adhesion reduction by activating the small guanosine triphosphatase Ras homolog family member J by releasing RhoGEF Tuba from direct binding to PlexinD1, thus mediating endothelial cell motility and filopodia retraction. Our study reveals that Sema3E/PlexinD1 signaling, which suppressed endothelial DLL4 expression, cell motility, and filopodia formation, is expected to be a novel druggable target for angiogenesis during poststroke progression.— Zhou, Y.‐F., Chen, A.‐Q., Wu, J.‐H., Mao, L., Xia, Y.‐P., Jin, H.‐J., He, Q.‐W., Miao, Q. R., Yue, Z.‐Y., Liu, X.‐L., Huang, M., Li, Y.‐N., Hu, B. Sema3E/PlexinD1 signaling inhibits postischemic angiogenesis by regulating endothelial DLL4 and filopodia formation in a rat model of ischemic stroke. FASEB J. 33, 4947–4961 (2019). http://www.fasebj.org

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