• Macrophage
• STAT3
• Tumor microenvironment
• VEGFB
• VEGFR1

• ALD
• VEGF
• brain death
• growth hormone
• ischemia-reperfusion
• liver transplantation

• EMT
• TME
• angiogenesis
• immunotherapy
• lung cancer

• Humans
• Epithelial-Mesenchymal Transition/immunology
• Tumor Microenvironment/immunology
• Lung Neoplasms/therapy
• Lung Neoplasms/immunology
• Lung Neoplasms/pathology
• Immunotherapy/methods
• Neovascularization, Pathologic/immunology
• Animals
• Angiogenesis

• GLUT2
• Insulin resistance
• NAFLD
• PI3K/AKT
• VEGFB

• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/pathology
• Insulin Resistance
• Animals
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction
• Humans
• Phosphatidylinositol 3-Kinases/metabolism
• Hep G2 Cells
• Vascular Endothelial Growth Factor B/metabolism
• Male
• Mice, Inbred C57BL
• Liver/metabolism
• Liver/pathology
• Diet, High-Fat
• Mice
• Disease Models, Animal
• Lipid Metabolism

• 2022JCYJ026 The Basic Research Project of Yantai Science and Technology Innovation and Development Plan
• 2023JCYJ068 The Basic Research Project of Yantai Science and Technology Innovation and Development Plan
• ZR202111250163 The Natural Science Foundation of Shandong province
• S202310440040 College Students' innovation and entrepreneurship training program
• College Students’ innovation and entrepreneurship training program

• endometrial receptivity
• recurrent implantation failure
• recurrent pregnancy loss
• thin endometrium
• transcriptomics

• AP 14870089 Science Committee of the Ministry of Science and High Education of the Republic of Kazakhstan

• endometrial receptivity
• recurrent implantation failure
• thin endometrium
• transcriptomics

• AP 14870089 Science Committee of the Ministry of Science and High Education of the Republic of Kazakhstan

• Adipogenesis
• Expression profile
• Lateolabrax maculatus
• Molecular characterization
• Vascular endothelial growth factor B

• Animals
• Bass/genetics
• Bass/metabolism
• Lipid Metabolism/genetics
• Vascular Endothelial Growth Factor B/metabolism
• Vascular Endothelial Growth Factor B/genetics
• Cloning, Molecular
• Amino Acid Sequence
• Phylogeny
• Liver/metabolism
• Gene Expression Regulation/drug effects
• Hepatocytes/metabolism
• Hepatocytes/drug effects
• Adipogenesis/genetics

• PI3K/Akt pathway
• Proliferation
• Pubertal mammary gland development
• VEGFB/VEGFR1 signaling

• Animals
• Mice
• Proto-Oncogene Proteins c-akt/metabolism
• Vascular Endothelial Growth Factor B
• Phosphatidylinositol 3-Kinases/metabolism
• Axitinib/pharmacology
• Receptors, Vascular Endothelial Growth Factor
• Cell Proliferation

• Alzheimer’s disease
• Angiogenesis
• Axitinib, PubChem CID: 6450551
• Cabozantinib, PubChem CID: 25102847
• Lenvatinib, PubChem CID: 9823820
• Parkinson’s disease
• Pazopanib, PubChem CID: 10113978
• Ponatinib: PubChem CID 24826799
• Regorafenib, PubChem CID: 11167602
• Sorafenib, PubChem CID: 216239
• Sunitinib, PubChem CID: 5329102
• VEGF-A
• VEGFR-1
• VEGFR-2
• Vandetanib, PubChem CID: 3081361

• Animals
• Parkinson Disease/drug therapy
• Alzheimer Disease/drug therapy
• Vascular Endothelial Growth Factor Receptor-1
• Central Nervous System
• Brain

Impaired glucose tolerance (IGT) is a homeostatic state between euglycemia and hyperglycemia and is considered an early high-risk state of diabetes. When IGT occurs, insulin sensitivity decreases, causing a reduction in insulin secretion and an increase in glucagon secretion. Recently, vascular endothelial growth factor B (VEGFB) has been demonstrated to play a positive role in improving glucose metabolism and insulin sensitivity. Therefore, we constructed a mouse model of IGT through high-fat diet feeding and speculated that VEGFB can regulate hyperglycemia in IGT by influencing insulin-mediated glucagon secretion, thus contributing to the prevention and cure of prediabetes.

To explore the potential molecular mechanism and regulatory effects of VEGFB on insulin-mediated glucagon in mice with IGT.

We conducted in vivo experiments through systematic VEGFB knockout and pancreatic-specific VEGFB overexpression. Insulin and glucagon secretions were detected via enzyme-linked immunosorbent assay, and the protein expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) was determined using western blot. Further, mRNA expression of forkhead box protein O1, phosphoenolpyruvate carboxykinase, and glucose-6 phosphatase was detected via quantitative polymerase chain reaction, and the correlation between the expression of proteins was analyzed via bioinformatics.

In mice with IGT and VEGFB knockout, glucagon secretion increased, and the protein expression of PI3K/AKT decreased dramatically. Further, in mice with VEGFB overexpression, glucagon levels declined, with the activation of the PI3K/AKT signaling pathway.

VEGFB/vascular endothelial growth factor receptor 1 can promote insulin-mediated glucagon secretion by activating the PI3K/AKT signaling pathway to regulate glucose metabolism disorders in mice with IGT.

• Vascular endothelial growth factor B
• Insulin-mediated
• Glucagon secretion
• Prediabetes
• Impaired glucose tolerance

Nonalcoholic fatty liver disease (NAFLD) refers to fatty liver disease caused by liver injury factors other than alcohol. The disease is characterized by diffuse fat infiltration, including simple steatosis (no inflammatory fat deposition), nonalcoholic fatty hepatitis, liver fibrosis, and so on, which may cause liver cirrhosis, liver failure, and even liver cancer in the later stage of disease progression. At present, the pathogenesis of NAFLD is still being studied. The "two-hit" theory, represented by lipid metabolism disorder and inflammatory reactions, is gradually enriched by the "multiple-hit" theory, which includes multiple factors, such as insulin resistance and adipocyte dysfunction. In recent years, vascular endothelial growth factor B (VEGFB) has been reported to have the potential to regulate lipid metabolism and is expected to become a novel target for ameliorating metabolic diseases, such as obesity and type 2 diabetes. This review summarizes the regulatory role of VEGFB in the onset and development of NAFLD and illustrates its underlying molecular mechanism. In conclusion, the signaling pathway mediated by VEGFB in the liver may provide an innovative approach to the diagnosis and treatment of NAFLD.

• Nonalcoholic fatty liver disease
• Vascular endothelial growth factor B
• "Two-hit" theory
• "Multiple-hit" theory
• Obesity

• Angiogenesis
• Antiangiogenic drugs
• Clinical treatment
• Signaling pathway
• Tumor

Non-tumor adjacent tissue plays a key role in colorectal cancer development, as well as chronic inflammation, but their role has not yet been dilucidated. In addition, inflammation is a process which is related to epithelial-mesenchymal transition and metastasis, but their changes across the different colorectal cancer stages are not fully studied. Understanding how these processes participate in all colorectal cancer phases can be key to a better understanding of the disease.

Chronic inflammation can induce malignant cell transformation, having an important role in all colorectal cancer (CRC) phases. Non-tumor adjacent tissue plays an important role in tumor progression, but its implication in CRC has not yet been fully elucidated. The aim was to analyze the expression of inflammatory, epithelial-mesenchymal transition (EMT), and metastasis-related proteins in both tumor and non-tumor adjacent tissues from CRC patients by western blot. Tumor tissue presented an increase in metastasis and EMT-related proteins compared to non-tumor adjacent tissue, especially in stage II. Tumor tissue stage II also presented an increase in inflammatory-related proteins compared to other stages, which was also seen in non-tumor adjacent tissue stage II. Additionally, the relapse-free survival study of Vimentin and VEGF-B expression levels in stage II patients showed that the higher the expression levels of each protein, the lower 10-year relapse-free survival. These could suggest that some metastasis-related signalling pathways may be activated in stage II in tumor tissue, accompanied by an increase in inflammation. Furthermore, non-tumor adjacent tissue presented an increase of the inflammatory status that could be the basis for future tumor progression. In conclusion, these proteins could be useful as biomarkers of diagnosis for CRC at early stages.

• colorectal cancer
• epithelial-mesenchymal transition
• inflammation
• metastasis
• non-tumor adjacent tissue
• tumor tissue

• Animals
• Human Umbilical Vein Endothelial Cells/metabolism
• Humans
• Ligands
• Mice
• Rats
• Receptors, Vascular Endothelial Growth Factor/metabolism
• Vascular Endothelial Growth Factor A/metabolism
• Vascular Endothelial Growth Factor B
• Vascular Endothelial Growth Factor Receptor-1/metabolism
• Vascular Endothelial Growth Factor Receptor-2/metabolism

• P30 EY001792 NEI NIH HHS
• R01 EY027912 NEI NIH HHS
• National Eye Institute
• Research to Prevent Blindness

It has been demonstrated that vascular endothelial growth factor B (VEGFB) and vascular endothelial growth factor receptor 1 (VEGFR1) play a vital role in regulating vascular biological function. However, the role of VEGFB and VEGFR1 in regulating fat deposition and skeletal muscle growth remains unclear. Therefore, this study was conducted to investigate the effects of VEGFB and VEGFR1 on fat deposition and skeletal muscle growth in mice. Our results showed that knockdown of VEGFB decreased body weight and iWAT index, stimulated the browning of mice iWAT with increased expression of UCP1, decreased the diameters of adipocytes, and elevated energy expenditure. In contrast, knockdown of VEGFB increased gastrocnemius (GAS) muscle index with increased proliferation of GAS muscle by expression of PCNA and Cyclin D1. Meanwhile, knockdown of endothelial VEGFR1 induced the browning of iWAT with increased expression of UCP1 and decreased diameters of adipocytes. By contrast, knockdown of endothelial VEGFR1 inhibited GAS muscle differentiation with decreased expression of MyoD. In conclusion, these results suggested that the loss of VEGFB/VEGFR1 signaling is associated with enhanced browning of inguinal white adipose tissue and skeletal muscle development. These results provided new insights into the regulation of skeletal muscle growth and regeneration, as well as fat deposition, suggesting the potential application of VEGFB/VEGFR1 as an intervention for the restriction of muscle diseases and obesity and related metabolic disorders.

• Adipose Tissue, Brown/metabolism
• Adipose Tissue, White/metabolism
• Animals
• Mice
• Mice, Inbred C57BL
• Muscle Development/genetics
• Muscle, Skeletal/metabolism
• Thermogenesis
• Vascular Endothelial Growth Factor A/metabolism
• Vascular Endothelial Growth Factor B/genetics
• Vascular Endothelial Growth Factor B/metabolism
• Vascular Endothelial Growth Factor Receptor-1/genetics
• Vascular Endothelial Growth Factor Receptor-1/metabolism

• VEGF B
• VEGF R1
• VEGF R2
• cancer
• cell migration
• pFAK
• papaverine

• Antineoplastic Agents
• Cell Line
• Cell Movement/drug effects
• Humans
• Neoplasms
• Papaverine/pharmacology
• Vascular Endothelial Growth Factor A/drug effects
• Vascular Endothelial Growth Factor A/metabolism
• Vascular Endothelial Growth Factors

• N00375 National Research Foundation
• N0059 National Research Foundation
• AON074 Struwig-Germeshuysen Cancer Research Fund
• A0V741 Cancer Association of South Africa
• A0W228 Cancer Association of South Africa
• A0W110 South African Medical Research Council
• AOR984 School of Medicine Research Committee, University of Pretoria

Type 2 diabetes (T2D) is characterized by insufficient insulin secretion caused by defective pancreatic β-cell function or insulin resistance, resulting in an increase in blood glucose. However, the mechanism involved in this lack of insulin secretion is unclear. The level of vascular endothelial growth factor B (VEGF-B) is significantly increased in T2D patients. The inactivation of VEGF-B could restore insulin sensitivity in db/db mice by reducing fatty acid accumulation. It is speculated that VEGF-B is related to pancreatic β-cell dysfunction and is an important factor affecting β-cell secretion of insulin. As an in vitro model of normal pancreatic β-cells, the MIN6 cell line can be used to analyze the mechanism of insulin secretion and related biological effects.

To study the role of VEGF-B in the insulin secretion signaling pathway in MIN6 cells and explore the effect of VEGF-B on blood glucose regulation.

The MIN6 mouse pancreatic islet β-cell line was used as the model system. By administering exogenous VEGF-B protein or knocking down VEGF-B expression in MIN6 cells, we examined the effects of VEGF-B on insulin secretion, Ca²⁺ and cyclic adenosine monophosphate (cAMP) levels, and the insulin secretion signaling pathway.

Exogenous VEGF-B inhibited the secretion of insulin and simultaneously reduced the levels of Ca²⁺ and cAMP in MIN6 cells. Exogenous VEGF-B also reduced the expression of phospholipase C gamma 1 (PLCγ1), phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (AKT), and other proteins in the insulin secretion pathway. Upon knockdown of VEGF-B, MIN6 cells exhibited increased insulin secretion and Ca²⁺ and cAMP levels and upregulated expression of PLCγ1, PI3K, AKT, and other proteins.

VEGF-B can regulate insulin secretion by modulating the levels of Ca²⁺ and cAMP. VEGF-B involvement in insulin secretion is related to the expression of PLCγ1, PI3K, AKT, and other signaling proteins. These results provide theoretical support and an experimental basis for the study of VEGF-B in the pathogenesis of T2D.

• Type 2 diabetes
• Insulin secretion
• MIN6 cells
• Vascular endothelial growth factor B
• Blood glucose regulation

Müller glia are important in retinal health and disease and are a major source of retinal VEGF-A. Of the different VEGF family members, the role of VEGF-A in retinal health and disease has been studied extensively. The potential contribution of other VEGF family members to retinal pathophysiology, however, remains poorly defined. This study aimed to understand the role of VEGF-B in Müller cell pathophysiology.

The expression of different VEGFs and their receptors in human MIO-M1 and mouse QMMuC-1 Müller cell lines and primary murine Müller cells was examined by RT-PCR, ELISA, and Western blot. The effect of recombinant VEGF-B or VEGF-B neutralization on Müller cell viability and survival under normal, hypoxic, and oxidative (4-hydroxynonenal [4-HNE]) conditions was evaluated by Alamar Blue, Yo-Pro uptake, and immunocytochemistry. The expression of glial fibrillary acidic protein, aquaporin-4, inward rectifying K⁺ channel subtype 4.1, glutamine synthetase, and transient receptor potential vanilloid 4 under different treatment conditions was examined by RT-PCR, immunocytochemistry, and Western blot. Transient receptor potential vanilloid 4 channel activity was assessed using a Fura-2–based calcium assay.

VEGF-B was expressed in Müller cells at the highest levels compared with other members of the VEGF family. VEGF-B neutralization did not affect Müller cell viability or functionality under normal conditions, but enhanced hypoxia– or 4-HNE–induced Müller cell death and decreased inward rectifying K⁺ channel subtype 4.1 and aquaporin-4 expression. Recombinant VEGF-B restored Müller cell glutamine synthetase expression under hypoxic conditions and protected Müller cells from 4-HNE–induced damage by normalizing transient receptor potential vanilloid 4 channel expression and activity.

Autocrine production of VEGF-B protects Müller cells under pathologic conditions.

• Erythropoietin
• VEGF
• excitotoxicity
• neuroprotection
• neurorestoration
• therapeutics.

• blood pressure
• metabolism
• non-alcoholic fatty liver disease
• renal dysfunction
• vascular endothelial growth factor B

• VEGFB
• neurite outgrowth
• neuronal survival
• peptide

• Conbercept
• Diabetic retinopathy
• Placenta growth factor
• Vascular endothelial growth factor

• Adult
• Aqueous Humor/metabolism
• Biomarkers/metabolism
• Diabetic Retinopathy/drug therapy
• Diabetic Retinopathy/metabolism
• Diabetic Retinopathy/pathology
• Female
• Humans
• Intravitreal Injections
• Male
• Membrane Proteins/metabolism
• Middle Aged
• Prospective Studies
• Recombinant Fusion Proteins/administration & dosage
• Vascular Endothelial Growth Factor A/metabolism

The response of endothelial cells to signaling stimulation is critical for vascular morphogenesis, homeostasis and function. Vascular endothelial growth factor-a (VEGFA) has been commonly recognized as a pro-angiogenic factor in vertebrate developmental, physiological and pathological conditions for decades. Here we report a novel finding that genetic ablation of CDP-diacylglycerol synthetase-2 (CDS2), a metabolic enzyme that controls phosphoinositide recycling, switches the output of VEGFA signaling from promoting angiogenesis to unexpectedly inducing vessel regression. Live imaging analysis uncovered the presence of reverse migration of the angiogenic endothelium in cds2 mutant zebrafish upon VEGFA stimulation, and endothelium regression also occurred in postnatal retina and implanted tumor models in mice. In tumor models, CDS2 deficiency enhanced the level of tumor-secreted VEGFA, which in-turn trapped tumors into a VEGFA-induced vessel regression situation, leading to suppression of tumor growth. Mechanistically, VEGFA stimulation reduced phosphatidylinositol (4,5)-bisphosphate (PIP2) availability in the absence of CDS2-controlled-phosphoinositide metabolism, subsequently causing phosphatidylinositol (3,4,5)-triphosphate (PIP3) deficiency and FOXO1 activation to trigger regression of CDS2-null endothelium. Thus, our data indicate that the effect of VEGFA on vasculature is context-dependent and can be converted from angiogenesis to vascular regression.

• C2C12
• VEGFB
• fatty acid
• lipid accumulation

• Animals
• Cell Line
• Fatty Acid Transport Proteins/genetics
• Fatty Acid Transport Proteins/metabolism
• Lipid Droplets/metabolism
• Lipid Metabolism
• Mice
• Muscle Fibers, Skeletal/drug effects
• Muscle Fibers, Skeletal/metabolism
• Oleic Acid/pharmacology
• Palmitic Acid/pharmacology
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
• Vascular Endothelial Growth Factor B/pharmacology

• Antioxidant
• Apoptosis
• Degenerative diseases
• Ocular disorders
• Oxidative stress
• VEGF-B

• Expression
• Expression quantitative trait loci
• Gene network
• Recombinant inbred
• Vascular endothelial growth factor

• nerve injury
• nerve regeneration
• p300
• resveratrol
• vascular endothelial growth factor

• ELISA
• VEGF-A
• VEGF-B
• neovascular diseases
• vitreous humor

• Aged
• Female
• Humans
• Male
• Neovascularization, Pathologic/metabolism
• Retinal Diseases/metabolism
• Retrospective Studies
• Vascular Endothelial Growth Factor A/blood
• Vascular Endothelial Growth Factor B/blood
• Vitreous Body/metabolism

Many types of cancer develop in close association with highly vascularized adipose tissues. However, the role of adipose pre-existing vascular beds on tumor growth and angiogenesis is unknown. Here we report that pre-existing microvascular density in tissues where tumors originate is a crucial determinant for tumor growth and neovascularization. In three independent tumor types including breast cancer, melanoma, and fibrosarcoma, inoculation of tumor cells in the subcutaneous tissue, white adipose tissue (WAT), and brown adipose tissue (BAT) resulted in markedly differential tumor growth rates and angiogenesis, which were in concordance with the degree of pre-existing vascularization in these tissues. Relative to subcutaneous tumors, WAT and BAT tumors grew at accelerated rates along with improved neovascularization, blood perfusion, and decreased hypoxia. Tumor cells implanted in adipose tissues contained leaky microvessel with poor perivascular cell coverage. Thus, adipose vasculature predetermines the tumor microenvironment that eventually supports tumor growth.

• adipose tissue
• angiogenesis
• microenvironment
• tumor growth
• vasculature

• Angiogenesis
• Neovascularization
• Ophthalmic disorders
• Placental growth factor (PIGF)
• Vascular endothelial growth factor A (VEGF-A)
• Vascular endothelial growth factor B (VEGF-B)

JSRV (Jaagsiekte Sheep Retrovirus) is a retrovirus inducing a transmissible lung adenocarcinoma in sheep and goats with predominantly lepidic and papillary lesions. This naturally occurring lung cancer in large animals shares many features with human pneumonic-type lung adenocarcinomas with predominant lepidic growth. The metastatic spread is rare in both human and animal cancers. This unique feature prompted us to decipher the angiogenesis pathway in these cancers. We focused on the levels of mRNA and proteins of genes implicated in the extension of JSRV-induced lung adenocarcinomas by studying their expression in lung cancers (n = 10) and normal lungs (n = 10) and in primary epithelial alveolar type II cells derived from cancers (n = 10) or normal lungs (n = 6). In parallel, we evaluated the levels of expression of key genes in lung tissues collected from lepidic (n = 13) or papillary (n = 5) human adenocarcinomas and, when available, adjacent normal lungs (n = 11). We measured the expression of the same key genes implicated in angiogenesis, lymphangiogenesis and degradation of the extracellular matrix. In ovine adenocarcinomas, VEGFR2 and VEGFD mRNA were downregulated in cancers; MMP9, TIMP1 and FGFR2 mRNA were overexpressed as compared to normal lungs. Importantly, VEGFA and VEGFR2 proteins were not expressed in JSRV-induced cancers. In human lepidic adenocarcinomas, VEGFA and VEGFR2 mRNA were weakly expressed and no VEGFR2 protein was detectable. Downregulation of key angiogenic players may contribute to the control of extra thoracic invasion of cancer cells in human and ovine pneumonic-type adenocarcinoma with predominant lepidic growth.

• VEGF-B
• cancer
• cardiovascular diseases
• diabetes
• neurodegenerative diseases

• VEGF-B
• fatty acids
• insulin resistance
• metabolic syndrome
• obesity
• type 2 diabetes

Vascular endothelial growth factor B (VEGF-B) is one of the enigmatic members of the VEGF family. The knowledge gap about VEGF-B expression and how its levels are altered in diabetic eyes were the focus of this investigation that was addressed by comparing and correlating vitreous VEGF-B between diabetic and non-diabetic patients. VEGF-B levels were measured by enzyme-linked immunosorbent assay in vitreous samples (n = 33) from diabetic (n = 25) and non-diabetic (n = 8) patients. Results were compared between groups. Optical coherence tomography from diabetic patients was evaluated for central retinal thickness (CRT) and macular volume (MV). Mean vitreous VEGF-B concentration was higher in diabetic (18.82 ± 1.44 pg/mL) vs. non-diabetic patients (17.90 ± 0.32 pg/mL) (p = 0.006), and in proliferative diabetic retinopathy (PDR) (19.03 ± 1.52 pg/mL) vs. non-PDR (NPDR) patients (18.18 ±0.96 pg/mL) (p = 0.025). In diabetic retinopathy (DR) patients, correlation between VEGF-B and CRT (μm) was positive and moderate: r_s = 0.441 (p ≤ 0.05) and the correlation between VEGF-B and MV (mm³) was positive and robust: r_s = 0.716 (p ≤ 0.01). VEGF-B levels are overexpressed in vitreous of diabetic patients, and the levels are higher in developed stages of DR. Correlation results show that CRT and MV increase with increased levels of VEGF-B. Targeting VEGF-B inhibition may have therapeutic beneficial implications.

• VEGF inhibition
• angiogenesis
• diabetic retinopathy
• enzyme-linked immunosorbent assay
• vascular endothelial growth factor-B
• vitreous humor

• Cerebral cortex
• Development
• Excitotoxicity
• Hippocampus
• Monosodium glutamate
• VEGF

• Cardiomyocyte metabolism
• Endothelial cell metabolism
• Heparanase
• Lipoprotein lipase
• Vascular endothelial growth factor

• PlGF
• VEGF-A
• VEGF-B
• neovascular glaucoma