Angiogenesis is regulated by the dynamic interaction between endothelial cells (ECs).Hippo-Yes-associated protein (YAP) signalling has emerged as a key pathway that controls organ size and tissue growth by mediating cell contact inhibition. However, the role of YAP in EC has not been defined yet. Here, we show expression of YAP in the developing front of mouse retinal vessels. YAP subcellular localization, phosphorylation and activity are regulated by VE-cadherin-mediated-EC contacts. This VE-cadherin-dependent YAP phosphorylation requires phosphoinositide 3-kinase-Akt activation. We further identify angiopoietin-2 (ANG-2) as a potential transcriptional target of YAP in regulating angiogenic activity of EC in vitro and in vivo. Overexpression of YAP-active form in EC enhances angiogenic sprouting, and this effect is blocked by ANG-2 depletion or soluble Tie-2 treatment. These findings implicate YAP as a critical regulator in angiogenesis and provide new insights into the mechanism coordinating junctional stability and angiogenic activation of ECs.

BackgroundBlood–brain barrier (BBB) breakdown and inflammation are critical events in ischemic stroke, contributing to aggravated brain damage. The BBB mainly consists of microvascular endothelial cells sealed by tight junctions to protect the brain from blood-borne substances. Thus, the maintenance of BBB integrity may be a potential target for neuroprotection. Sac-1004, a pseudo-sugar derivative of cholesterol, enhances the endothelial barrier by the stabilization of the cortical actin ring.ResultsHere, we report on the protective effects of Sac-1004 on cerebral ischemia-reperfusion (I/R) injury. Treatment with Sac-1004 significantly blocked the interleukin-1β-induced monolayer hyperpermeability of human brain microvascular endothelial cells (HBMECs), loss of tight junctions, and formation of actin stress fiber. Sac-1004 suppressed the expression of adhesion molecules, adhesion of U937 cells, and activation of nuclear factor-κB in HBMECs. Using a rat model of transient focal cerebral ischemia, it was shown that Sac-1004 effectively ameliorated neurological deficits and ischemic damage. In addition, Sac-1004 decreased BBB leakage and rescued tight junction-related proteins. Moreover, the staining of CD11b and glial fibrillary acidic protein showed that Sac-1004 inhibited glial activation.ConclusionsTaken together, these results demonstrate that Sac-1004 has neuroprotective activities through maintaining BBB integrity, suggesting that it is a great therapeutic candidate for stroke.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0897-3) contains supplementary material, which is available to authorized users.

Background The aim of this study was to predict isocitrate dehydrogenase (IDH) genotypes of gliomas using an interpretable deep learning application for dynamic susceptibility contrast (DSC) perfusion MRI. Methods Four hundred sixty-three patients with gliomas who underwent preoperative MRI were enrolled in the study. All the patients had immunohistopathologic diagnoses of either IDH-wildtype or IDH-mutant gliomas. Tumor subregions were segmented using a convolutional neural network followed by manual correction. DSC perfusion MRI was performed to obtain T2* susceptibility signal intensity-time curves from each subregion of the tumors: enhancing tumor, non-enhancing tumor, peritumoral edema, and whole tumor. These, with arterial input functions, were fed into a neural network as multidimensional inputs. A convolutional long short-term memory model with an attention mechanism was developed to predict IDH genotypes. Receiver operating characteristics analysis was performed to evaluate the model. Results The IDH genotype predictions had an accuracy, sensitivity, and specificity of 92.8%, 92.6%, and 93.1%, respectively, in the validation set (area under the curve [AUC], 0.98; 95% confidence interval [CI], 0.969–0.991) and 91.7%, 92.1%, and 91.5%, respectively, in the test set (AUC, 0.95; 95% CI, 0.898–0.982). In temporal feature analysis, T2* susceptibility signal intensity-time curves obtained from DSC perfusion MRI with attention weights demonstrated high attention on the combination of the end of the pre-contrast baseline, up/downslopes of signal drops, and/or post-bolus plateaus for the curves used to predict IDH genotype. Conclusions We developed an explainable recurrent neural network model based on DSC perfusion MRI to predict IDH genotypes in gliomas.

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Cell-to-cell junctions are critical for the formation of endothelial barriers, and its disorganization is required for sprouting angiogenesis. Members of the angiomotin (AMOT) family have emerged as key regulators in the control of endothelial cell (EC) junction stability and permeability. However, the underlying mechanism by which the AMOT family is regulated in ECs remains unclear. Here we report that HECW2, a novel EC ubiquitin E3 ligase, plays a critical role in stabilizing endothelial cell-to-cell junctions by regulating AMOT-like 1 (AMOTL1) stability. HECW2 physically interacts with AMOTL1 and enhances its stability via lysine 63-linked ubiquitination. HECW2 depletion in human ECs decreases AMOTL1 stability, loosening the cell-to-cell junctions and altering subcellular localization of yes-associated protein (YAP) from cytoplasm into the nucleus. Knockdown of HECW2 also results in increased angiogenic sprouting, and this effect is blocked by depletion of ANG-2, a potential target of YAP. These results demonstrate that HECW2 is a novel regulator of angiogenesis and provide new insights into the mechanisms coordinating junction stability and angiogenic activation in ECs.