ArticleDiabetologia2017
Enhanced VEGF signalling mediates cerebral neovascularisation via downregulation of guidance protein ROBO4 in a rat model of diabetes.
Article in Diabetologia, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 31 citations in OpenAlex.
- Association of cognition with leptin and vascular endothelial growth factor in individuals with type 2 diabetes mellitus.Obesity (Silver Spring, Md.) · 2022Trial
- Diabetic cerebral microvascular disorder: from key pathologies to targeted interventions.Annals of medicine · 2026Review
- Deletion of Robo4 worsens neuroinflammation in a mouse model of Alzheimer's disease.Physiological reports · 2026Article
- Insights into the potential pathogenesis and therapeutic implications of ferroptosis in brain microvascular endothelial cells during stroke.Frontiers in immunology · 2026Review
- Ets2 Exacerbates Diabetic Retinopathy by Aggravating the Proliferation of Endothelial Cells and Inflammatory Response.Biochemical genetics · 2025Article
- Robo4 inhibits neovascularization in oxygen-induced retinopathy by regulating ARF6 and VEGF.Human cell · 2025Article
- Ligand-Receptor Analysis of Brain Cell Type Marker Data Reveals Intricate Endothelial Interaction.Annals of neurosciences · 2025Article
- Zi Shen Wan Fang repaired blood-brain barrier integrity in diabetic cognitive impairment mice via preventing cerebrovascular cells senescence.Chinese medicine · 2024Article
- SARS-CoV-2 Spike Protein Intensifies Cerebrovascular Complications in Diabetic hACE2 Mice through RAAS and TLR Signaling Activation.International journal of molecular sciences · 2023Article
- Robo4 inhibits gamma radiation-induced permeability of a murine microvascular endothelial cell by regulating the junctions.Cellular & molecular biology letters · 2023Article
- Vascular contributions to cognitive impairment/dementia in diabetes: role of endothelial cells and pericytes.American journal of physiology. Cell physiology · 2022Review
- Contralesional angiotensin type 2 receptor activation contributes to recovery in experimental stroke.Neurochemistry international · 2022Article
- GLP-1 receptor nitration contributes to loss of brain pericyte function in a mouse model of diabetes.Diabetologia · 2022Article
- Oxymatrine Alleviates Hyperglycemic Cerebral Ischemia/Reperfusion Injury via Protecting Microvessel.Neurochemical research · 2022Article
- Efficiency ofExperimental and therapeutic medicine · 2021Article
- Regulatory mechanisms of Robo4 and their effects on angiogenesis.Bioscience reports · 2019Review
- Enhanced ROBO4 is mediated by up-regulation of HIF-1α/SP1 or reduction in miR-125b-5p/miR-146a-5p in diabetic retinopathy.Journal of cellular and molecular medicine · 2019Article
- Upregulated VEGF and Robo4 correlate with the reduction of miR-15a in the development of diabetic retinopathy.Endocrine · 2019Article
- Brain Vasculature and Cognition.Arteriosclerosis, thrombosis, and vascular biology · 2019Review
- Inhibition of Ephrin-B2 in brain pericytes decreases cerebral pathological neovascularization in diabetic rats.PloS one · 2019Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
aims/hypothesisDiabetes promotes cerebral neovascularisation via increased vascular endothelial growth factor (VEGF) angiogenic signalling. Roundabout-4 (ROBO4) protein is an endogenous inhibitor of VEGF signalling that stabilises the vasculature. Yet, how diabetes affects ROBO4 function remains unknown. We hypothesised that increased VEGF signalling in diabetes decreases ROBO4 expression and function via binding of ROBO4 with VEGF-activated β3 integrin and that restoration of ROBO4 expression prevents/repairs cerebral neovascularisation in diabetes.
methodsROBO4 protein expression in a rat model of type 2 diabetes (Goto-Kakizaki [GK] rats) was examined by western blotting and immunohistochemistry. ROBO4 was locally overexpressed in the brain and in primary brain microvascular endothelial cells (BMVECs). GK rats were treated with SKLB1002, a selective VEGF receptor-2 (VEGFR-2) antagonist. Cerebrovascular neovascularisation indices were determined using a FITC vascular space-filling model. Immunoprecipitation was used to determine ROBO4-β3 integrin interaction.
resultsROBO4 expression was significantly decreased in the cerebral vasculature as well as in BMVECs in diabetes (p < 0.05). Silencing Robo4 increased the angiogenic properties of control BMVECs (p < 0.05). In vivo and in vitro overexpression of ROBO4 inhibited VEGF-induced angiogenic signalling and increased vessel maturation. Inhibition of VEGF signalling using SKLB1002 increased ROBO4 expression (p < 0.05) and reduced neovascularisation indices (p < 0.05). Furthermore, SKLB1002 significantly decreased ROBO4-β3 integrin interaction in diabetes (p < 0.05). CONCLUSIONS/
interpretationOur study identifies the restoration of ROBO4 and inhibition of VEGF signalling as treatment strategies for diabetes-induced cerebral neovascularisation.
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