Pericyte loss is an early characteristic change in diabetic retinopathy (DR). Despite accumulating evidence that hyperglycemia-induced angiopoietin 2 (Ang2) has a central role in pericyte loss, the precise molecular mechanism has not been elucidated. This study investigated the role of Ang2 in pericyte loss in DR. We demonstrated that pericyte loss occurred with Ang2 increase in the diabetic mouse retina and that the source of Ang2 could be the endothelial cell. Ang2 induced pericyte apoptosis via the p53 pathway under high glucose, whereas Ang2 alone did not induce apoptosis. Integrin, not Tie-2 receptor, was involved for Ang2-induced pericyte apoptosis under high glucose as an Ang2 receptor. High glucose changed the integrin expression pattern, which increased integrin α3 and β1 in the pericyte. Furthermore, Ang2-induced pericyte apoptosis in vitro was effectively attenuated via p53 suppression by blocking integrin α3 and β1. Although intravitreal injection of Ang2 induced pericyte loss in C57BL/6J mice retina in vivo, intravitreal injection of anti-integrin α3 and β1 antibodies attenuated Ang2-induced pericyte loss. Taken together, Ang2 induced pericyte apoptosis under high glucose via α3β1 integrin. Glycemic control or blocking Ang2/integrin signaling could be a potential therapeutic target to prevent pericyte loss in early DR.

Vascular inflammation is characteristic feature of diabetic retinopathy. In diabetic retina, a variety of the pro-inflammatory cytokines are elevated and involved in endothelial dysfunction. STAT3 transcription factor has been implicated in mediating cytokine signaling during vascular inflammation. However, whether and how STAT3 is involved in the direct regulation of the endothelial permeability is currently undefined. Our studies revealed that IL-6-induced STAT3 activation increases retinal endothelial permeability and vascular leakage in retinas of mice through the reduced expression of the tight junction proteins ZO-1 and occludin. In a co-culture model with microglia and endothelial cells under a high glucose condition, the microglia-derived IL-6 induced STAT3 activation in the retinal endothelial cells, leading to increasing endothelial permeability. In addition, IL-6-induced STAT3 activation was independent of ROS generation in the retinal endothelial cells. Moreover, we demonstrated that STAT3 activation downregulates the ZO-1 and occludin levels and increases the endothelial permeability through the induction of VEGF production in retinal endothelial cells. These results suggest the potential importance of IL-6/STAT3 signaling in regulating endothelial permeability and provide a therapeutic target to prevent the pathology of diabetic retinopathy. J. Cell. Physiol. 232: 1123-1134, 2017. © 2016 Wiley Periodicals, Inc.

Inner and outer blood‐retinal barriers (BRBs), mainly composed of retinal endothelial cells and retinal pigment epithelial (RPE) cells, respectively, maintain the integrity of the retinal tissues. In this study, we aimed to investigate the mechanisms of the outer BRB disruption regarding the interaction between RPE and microglia. In mice with high‐fat diet‐induced obesity and streptozotocin‐induced hyperglycemia, microglia accumulated on the RPE layer, as in those after intravitreal injection of interleukin (IL)‐6, which is elevated in ocular fluids of patients with diabetic retinopathy. Although IL‐6 did not directly affect the levels of zonula occludens (ZO)‐1 and occludin in RPE cells, IL‐6 increased VEGFA mRNA in RPE cells to recruit microglial cells. In microglial cells, IL‐6 upregulated the mRNA levels of MCP1, MIP1A, and MIP1B, to amplify the recruitment of microglial cells. In this manner, IL‐6 modulated RPE and microglial cells to attract microglial cells on RPE cells. Furthermore, IL‐6‐treated microglial cells produced and secreted tumor necrosis factor (TNF)‐α, which activated NF‐κB and decreased the levels of ZO‐1 in RPE cells. As STAT3 inhibition reversed the effects of IL‐6‐treated microglial cells on the RPE monolayer in vitro, it reduced the recruitment of microglial cells and the production of TNF‐α in RPE tissues in streptozotocin‐treated mice. Taken together, IL‐6‐treated RPE and microglial cells amplified the recruitment of microglial cells and IL‐6‐treated microglial cells produced TNF‐α to disrupt the outer BRB in diabetic retinopathy.

It can be concluded that sinus augmentation with ErhBMP-2 carrying BCP carrier did not enhance bone regeneration compared to the conventional treatment using deproteinized bovine bone at 24 weeks after the surgery.

The results suggested that DPBM might produce comparable bone formation and volumetric stability with DBBM in maxillary sinus grafting, however, further clinical study with longer-term periods and larger sample sizes should be needed for confirming this suggestion.

Although titanium-based implants are widely used in orthopedic and dental clinics, improved osseointegration at the bone–implant interface is still required.

This study unveiled an immunomodulatory role of STRO-1 CD146 PDLSCs in negatively regulating DC-mediated T-cell immune responses, demonstrating their potential to be utilized in promising new stem cell therapies.

Pericytes (PCs) are crucial in maintaining the quiescence of endothelial cells (ECs) and the integrity of EC tight junctions. Especially in diabetic retinopathy (DR), PC loss is one of the early pathologic changes in capillaries of diabetic retinas. Thus, preventing PC loss is beneficial for attenuating vision impairment in patients with DR. Although many studies have revealed the mechanism of PC loss in retinas, little is known about the mechanisms that increase PC survival. We focused on the effect of β-adrenergic receptor agonists (β-agonists) on PC loss in diabetic retinas. In this study, β-agonists increased the cell viability of PCs by increasing PC survival and proliferation. Mechanistically, β-agonist-induced protein kinase B activation in PCs reduced PC apoptosis in response to various stimuli. β2-agonists more potently increased PC survival than β1-agonists. β2-Agonist reduced vascular leakage and PC loss in retinas of mice with streptozotocin-induced diabetes. In cocultures of PCs and ECs, β2-agonists restored the altered permeability and ZO-1 expression in ECs induced by PC loss. We concluded that β-agonists, especially β2-agonists, increase PC survival, thereby preventing diabetes-induced PC loss in retinas. These results provide a potential therapeutic benefit of β-agonists for preventing PC loss in DR.-Yun, J.-H., Jeong, H.-S., Kim, K.-J., Han, M. H., Lee, E. H., Lee, K., Cho, C.-H. β-Adrenergic receptor agonists attenuate pericyte loss in diabetic retinas through Akt activation.