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Promoting endothelial cell (EC) proliferation and angiogenesis after indirect revascularization surgery is crucial for decreasing the stroke rate in moyamoya patients. However, the role of delta-like factor 1 (DLK1) in regulating EC proliferation in chronically ischaemic brains and the specific mechanisms remain unclear. Therefore, we compared the expression levels of DLK1 in the dura mater (DM) tissues of patients with moyamoya disease and patients with aneurysms, and dual luciferase reporter and RNA binding protein immunoprecipitation assays were conducted to determine whether DLK1 is a target gene of miR-126-5p. The effect of DLK1 on EC proliferation and the interaction between DLK1 and miR-126-5p were explored in vitro. Then, we established an animal model of two-vessel occlusion together with encephalo-myo-synangiosis (2VO+EMS). The temporalis muscles (TMs) of the animals were transfected with DLK1 lentiviral RNA (Lv-DLK1) and short hairpin RNA (sh-DLK1) to compare the DLK1 expression, angiogenesis (CD31 count), and numbers of vacuoles and impaired tight junctions in the ECs of TM-covered chronically ischaemic brains as well as the cognitive improvement in each group. DLK1 expression was lower in the DM tissues of moyamoya patients than in those of the aneurysm patients, and DLK1 was identified as a target gene of miR-126-5p. In vitro, DLK1 inhibited EC proliferation, migration and angiogenesis and exerted effects opposite those of miR-126-5p. In 2VO+EMS rats, compared to the control transfection, the TM transfection of Lv-DLK1 induced significantly higher DLK1 expression and worse angiogenesis in the TM-covered ischaemic brain as well as less extensive cognitive improvement, while the transfection of sh-DLK1 into the TM had the opposite effects. In summary, DLK1, a target gene of miR-126-5p, negatively regulates angiogenesis in chronically ischaemic brains and is expected to be a new target to improve the efficacy of indirect revascularization surgery and the prognosis of moyamoya patients.

Background miR-126-5p plays an important role in promoting endothelial cell (EC) proliferation. We thus explored whether miR-126-5p can promote EC proliferation and angiogenesis in chronically ischemic brains (CIBs). Results Improved revascularization in moyamoya patients was correlated with upregulated miR-126-5p expression in the TM and DM. In vitro experiments showed that miR-126-5p promoted EC proliferation through the PI3K/Akt pathway. CIBs from the agomir group exhibited significantly higher p-Akt, VEGF, CD31 and eNOS expression compared with the control CIBs. The ICBP and the RCF were significantly better in the agomir compared with the control group. Conclusion Increasing miR-126-5p expression in the TM can promote EC proliferation and angiogenesis in CIBs of 2VO+EMS rats through the PI3K/Akt pathway. Methods We assessed the correlation between revascularization and miR-126-5p expression in the temporal muscle (TM) and dura mater (DM) of moyamoya patients. The effect of miR-126-5p on EC proliferation and downstream signaling pathways was explored in vitro. We established an animal model of two-vessel occlusion plus encephalo-myo-synangiosis (2VO+EMS), transfected the TM with miR-126-5p agomir/antagomir, compared the expression of miR-126-5p and relevant downstream cytokines in brain tissue among different groups, and investigated the improvement in cerebral blood perfusion (ICBP) and the recovery of cognitive function (RCF).

Background Basic research on the factors influencing indirect anastomosis formation in a 2-vessel occlusion plus encephalo-myo-synangiosis (2VO + EMS) rat model is conducive to improving the efficacy of indirect revascularization surgery in the clinic. However, the time point at which anastomosis between the rat temporal muscle (TM) and brain naturally has the greatest effect after encephalo-myo-synangiosis (EMS) remains unknown. Therefore, we conducted this study to explore the peak time of indirect anastomosis formation in the 2VO + EMS rat model. Methods Forty 2VO + EMS rats were randomly divided into five groups (n=8) according to the length of time (by week) after EMS, and 2VO rats were used as the control group (n=8). The expression of vascular endothelial growth factor (VEGF) and CD31 on the EMS side of the brain, perfusion ratio [improvement of cerebral blood perfusion (CBP) on the EMS side] and Morris water maze (MWM) results were compared between groups. Furthermore, the trends of the above variables were explored over weeks. Results Overall, the expression of VEGF and CD31, the perfusion ratio and the cognitive improvement in the 2VO + EMS rat model gradually increased over weeks after EMS. The VEGF and CD31 expression (as detected by immunofluorescence), perfusion ratio and number of times crossing the platform area peaked at 4 weeks after EMS. In addition, both the escape latency and the time spent in the target quadrant peaked in the fifth week after EMS. Conclusions After establishing the 2VO + EMS rat model, the degree of endothelial cell (EC) proliferation and CBP improvement on the EMS side of the brain peaked at 4 weeks after EMS, whereas the cognitive improvement peaked in the fifth week.

Deficits in astrocytes function contribute to major depressive disorder (MDD) and suicide, but it remains unclear the therapeutic effect of directly reactivating astrocyte in depression. Here, specific gain and loss of astrocytic cell functions in the medial prefrontal cortex (mPFC) bidirectionally regulates depression-like symptoms. Remarkably, recombinant human Thrombospondin-1 (rhTSP1), an astrocyte-secreted protein, exerted rapidly antidepressant-like actions through mPFC TH/dopamine/D2R pathways, but not D1R. TSP1 in the mPFC might have potential as a target for treating clinical depression.