• Common bile duct ligation
• Hypoxemia
• Intrapulmonary vascular dilations
• Liver cirrhosis
• Partial portal vein ligation
• Portal hypertension
• Pulmonary endothelial dysfunction
• VEGF

• Chronic liver disease
• Cirrhosis
• Decompensation
• Mesenteric tissue
• Portal hypertension

• Animals
• Portal Pressure/drug effects
• Hypertension, Portal/drug therapy
• Hypertension, Portal/physiopathology
• Male
• Splanchnic Circulation/drug effects
• Mice
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/physiopathology
• Liver/drug effects
• Liver/blood supply
• Liver/metabolism
• Liver/pathology
• Mice, Inbred C57BL
• Butyrates/pharmacology
• Butyrates/therapeutic use
• Disease Models, Animal
• Endothelial Cells/drug effects
• Endothelial Cells/metabolism

• attention deficit hyperactivity disorder
• autism
• cerebral palsy
• neurodevelopment
• offspring
• pathophysiological mechanisms
• preeclampsia
• spectrum disorder

• Pregnancy
• Animals
• Child
• Humans
• Female
• Autism Spectrum Disorder/etiology
• Mothers
• Placenta
• Hypertension
• Pre-Eclampsia

• Disease
• Fibrosis
• Integrative aspects of cell biology
• Model organism
• Transcriptomics

• angiogenesis
• bile acids
• biliary fibrosis
• ductular reaction
• hepatic stellate cells
• immune cells
• portal fibroblasts

• Humans
• Endothelial Cells/pathology
• Cholestasis/pathology
• Liver Diseases/pathology
• Fibrosis

• IK2 BX005306 BLRD VA

• cancer microenvironment
• pancreatic cancer
• tumour immunology

• Angiogenesis
• Biomaterials
• Mesenchymal stem cells
• Natural rubber latex
• Skeletal muscle

• Humans
• Regeneration
• Muscle, Skeletal/blood supply
• Muscle, Skeletal/physiology
• Neovascularization, Physiologic/drug effects
• Animals
• Biocompatible Materials/pharmacology
• MicroRNAs/genetics

• CH/15/1/31199 British Heart Foundation

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a painful recurrent condition characterized by the discomfort of the bladder, and current treatment options have limited effectiveness. Prolotherapy is a well-known treatment that involves the injection of non-biologic solutions to reduce pain and/or promote proliferation of soft tissue, and dextrose is the most common injectate. This study investigated the effects of dextrose prolotherapy in a rat model of IC/BPS and patients with IC/BPS. We used cyclophosphamide to induce IC/BPS in rats, and intravesical instillation of 10% dextrose solution was performed. After 1 week, we conducted a urodynamic test, bladder staining, and ECM-related gene expression analysis to examine the treatment’s efficacy. We found that dextrose treatment could recover the instability of the bladder, reduce frequent urination, and improve the glycosaminoglycan layer regeneration and the bladder wall thickness along with a significant intense expression of CD44 receptors. Furthermore, we enrolled 29 IC/BPS patients with previous hyaluronic acid/Botox treatment for more than 6 months with remained unchanged condition. In this study, they received intravesical injections of 10% dextrose solution followed by assessments for up to 12 weeks. Patient characteristics and a 3-day voiding diary before treatment were recorded. Patient responses were examined using IC/BPS-related questionnaires. Moreover, expressions of growth factors and cytokines were analyzed. The results demonstrated that dextrose prolotherapy in patients with IC/BPS reduced the frequency of treatment over time, with the mean number of treatments being 3.03 ± 1.52, and significantly reduced the incidence of nocturia and questionnaire scores associated with symptoms. Dextrose prolotherapy significantly enhanced EGF level and, in contrast, reduced the level of HGF, PIGF-1, and VEGF-D after several weeks following treatment. The cytokine analysis showed that the expressions of IL-12p70 and IL-10 were significantly up-regulated after dextrose prolotherapy in IC/BPS patients. The levels of most growth factors and cytokines in IC/BPS patients had no significant difference and showed a similar tendency as time progressed when compared to healthy controls. Overall, the alteration of growth factors and cytokines exhibited safe treatment and potential stimulation of tissue remodeling. In summary, our study demonstrated that dextrose prolotherapy is a promising treatment strategy for IC/BPS disease management.

• bladder pain syndrome
• dextrose prolotherapy
• hyaluronic acid receptor
• immune system
• inflammation
• interstitial cystitis

• cholangiocarcinoma
• hepatic fibrosis

• Animals
• Antibodies, Monoclonal/pharmacology
• Bile Duct Neoplasms/metabolism
• Bile Duct Neoplasms/pathology
• Cancer-Associated Fibroblasts/metabolism
• Cell Line, Tumor
• Cholangiocarcinoma/metabolism
• Cholangiocarcinoma/pathology
• Disease Progression
• Drug Resistance, Neoplasm
• Humans
• Hypoxia/metabolism
• Mice
• Placenta Growth Factor/antagonists & inhibitors
• Placenta Growth Factor/metabolism

• P01 CA261669 NCI NIH HHS
• F31 CA221073 NCI NIH HHS
• P01 CA080124 NCI NIH HHS
• R01 CA208205 NCI NIH HHS
• R41 CA213678 NCI NIH HHS
• R35 CA197743 NCI NIH HHS
• Cholangiocarcinoma Research Foundation
• Harvard Ludwig Cancer Center
• U.S. Department of Defense
• Cancéropôle PACA
• Romanian Ministry of Research and Innovation, CCCDI–UEFISCDI
• Alexander von Humboldt-Stiftung
• Advanced Medical Research Foundation
• Jane’s Trust Foundation
• National Cancer Institute
• National Foundation for Cancer Research
• Astellas Foundation for Research on Metabolic Disorders
• Uehara Memorial Foundation

• Hepatocellular carcinoma
• Lenvatinib
• Liver circulation
• Liver cirrhosis
• Prognosis
• Sonazoid

• ACE2, angiogenesis-converting enzyme 2
• ACLF, acute-on-chronic liver failure
• AT1R, angiotensin II type I receptor
• CCL2, chemokine (C-C motif) ligand 2
• CCl4, carbon tetrachloride
• CLD, chronic liver disease
• CSPH, clinically significant portal hypertension
• Dll4, delta like canonical Notch ligand 4
• ECM, extracellular matrix
• EUS, endoscopic ultrasound
• FXR
• FXR, farnesoid X receptor
• HCC, hepatocellular carcinoma
• HRS, hepatorenal syndrome
• HSC
• HSCs, hepatic stellate cells
• HVPG, hepatic venous pressure gradient
• Hsp90, heat shock protein 90
• JAK2, Janus kinase 2
• KO, knockout
• LSEC
• LSEC, liver sinusoidal endothelial cells
• MLCP, myosin light-chain phosphatase
• NET, neutrophil extracellular trap
• NO
• NO, nitric oxide
• NSBB
• NSBBs, non-selective beta blockers
• PDE, phosphodiesterase
• PDGF, platelet-derived growth factor
• PIGF, placental growth factor
• PKG, cGMP-dependent protein kinase
• Rho-kinase
• TIPS
• TIPS, transjugular intrahepatic portosystemic shunt
• VCAM1, vascular cell adhesion molecule 1
• VEGF
• VEGF, vascular endothelial growth factor
• angiogenesis
• eNOS, endothelial nitric oxide synthase
• fibrosis
• liver stiffness
• statins
• β-Arr2, β-arrestin 2
• β1-AR, β1-adrenergic receptor
• β2-AR, β2-adrenergic receptor

• hepatic stellate cell
• liver sinusoidal endothelial cell
• Kupffer cell
• hepatic microenvironment
• intercellular interaction

• Capillaries/metabolism
• Capillaries/pathology
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Hepatic Stellate Cells/metabolism
• Hepatic Stellate Cells/pathology
• Hepatocytes/metabolism
• Hepatocytes/pathology
• Humans
• Kupffer Cells
• Liver/metabolism
• Liver/pathology
• Liver Cirrhosis/genetics
• Liver Cirrhosis/pathology
• Lung Injury/genetics
• Lung Injury/pathology
• Signal Transduction/genetics

• National Natural Science Foundation of China

• PDGFRβ
• gold nanoparticles
• hepatic stellate cells
• liver fibrosis
• photothermal therapy

• Animals
• Hepatic Stellate Cells/pathology
• Hyperthermia
• Liver/pathology
• Liver Cirrhosis/pathology
• Liver Cirrhosis/therapy
• Mice
• Receptor, Platelet-Derived Growth Factor beta

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, exposing to the risk of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Angio-genesis is a complex process leading to the development of new vessels from pre-existing vessels. Angiogenesis is triggered by hypoxia and inflammation and is driven by the action of proangiogenic cytokines, mainly vascular endothelial growth factor (VEGF). In this review, we focus on liver angiogenesis associated with NAFLD and analyze the evidence of liver angiogenesis in animal models of NAFLD and in NAFLD patients. We also report the data explaining the role of angiogenesis in the progression of NAFLD and discuss the potential of targeting angiogenesis, notably VEGF, to treat NAFLD.

• liver sinusoidal endothelial cells
• non-alcoholic steatohepatitis
• vascular endothelial growth factor

• Angiogenesis
• HCC
• liver cirrhosis
• liver fibrosis
• progression

• Angiogenesis
• Cirrhosis
• HVPG
• PLGF
• Portal-hypertensive gastropathy
• SFLT1

• Kupffer cells
• angiogenesis
• hepatic stellate cells
• macrophages
• vascular endothelial growth factor

• APJ
• CB1
• CB2
• apelin
• endocannabinoids
• liver fibrosis

• Animals
• Antioxidants/administration & dosage
• Cerium/administration & dosage
• Down-Regulation
• Endothelial Cells/drug effects
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Inflammation/metabolism
• Inflammation/pathology
• Inflammation/therapy
• Interleukin-6/genetics
• Liver Cirrhosis, Experimental/metabolism
• Liver Cirrhosis, Experimental/pathology
• Liver Cirrhosis, Experimental/therapy
• Macrophages/drug effects
• Macrophages/metabolism
• Macrophages/pathology
• Male
• Metal Nanoparticles/administration & dosage
• Oxidative Stress/drug effects
• Portal Vein/drug effects
• Portal Vein/metabolism
• Portal Vein/pathology
• Rats
• Rats, Wistar
• Reactive Oxygen Species/metabolism
• Transcriptome

• Angiogenesis
• Hepatic venous pressure gradient
• Liver cirrhosis
• Nogo-A
• Placental growth factor
• Portal hypertension

• Adult
• Biomarkers/blood
• Case-Control Studies
• Elasticity Imaging Techniques
• Female
• Humans
• Hypertension, Portal/blood
• Hypertension, Portal/diagnosis
• Hypertension, Portal/etiology
• Liver/blood supply
• Liver/diagnostic imaging
• Liver Cirrhosis/blood
• Liver Cirrhosis/complications
• Male
• Middle Aged
• Nogo Proteins/blood
• Placenta Growth Factor/blood
• Predictive Value of Tests
• Prognosis
• Prospective Studies
• Severity of Illness Index

• Angiogenesis
• Capillarization
• Endothelial dysfunction
• Endothelium
• Steatosis

• Biomarkers
• Gas6
• HGF
• Liver fibrosis
• PlGF
• Staging

• Connexin 43
• Notch-1
• VEGFR-1/flt-1
• confocal immunofluorescence
• fibrosis
• myofibroblasts
• platelet-rich plasma (PRP)
• transforming growth factor (TGF)-β1/Smad3
• vascular endothelial growth factor (VEGF)-A
• α-smooth muscle actin

• VEGF-E
• VEGFR-2
• orf virus
• scar
• skin
• wound healing

Despite a considerable focus on the adverse effects of silver nanoparticles (AgNPs) in recent years, studies on the potential long-term effects of AgNPs are scarce. The aim of this study was to explore the effects of AgNPs following repeated low-dose, long-term exposure of human bronchial epithelial cells. To this end, the human BEAS-2B cell line was exposed to 1 µg/mL AgNPs (10 nm) for 6 weeks followed by RNA-sequencing (RNA-Seq) as well as genome-wide DNA methylation analysis. The transcriptomics analysis showed that a substantial number of genes (1717) were differentially expressed following AgNP exposure whereas only marginal effects on DNA methylation were observed. Downstream analysis of the transcriptomics data identified several affected pathways including the ‘fibrosis’ and ‘epithelial-mesenchymal transition’ (EMT) pathway. Subsequently, functional validation studies were performed using AgNPs of two different sizes (10 nm and 75 nm). Both NPs increased collagen deposition, indicative of fibrosis, and induced EMT, as evidenced by an increased invasion index, anchorage independent cell growth, as well as cadherin switching. In conclusion, using a combination of RNA-Seq and functional assays, our study revealed that repeated low-dose, long-term exposure of human BEAS-2B cells to AgNPs is pro-fibrotic, induces EMT and cell transformation.

Liver dysfunction is a major problem in patients with severe preeclampsia (PE), hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, or in patients receiving anti-vascular endothelial growth factor (VEGF) therapy. Excessive soluble fms-like tyrosine kinase 1 (sFlt1) that antagonizes VEGF has been implicated in the pathogenesis of PE. VEGF increases the expression of endothelial nitric oxide synthase (eNOS) and activates it. eNOS polymorphisms that cause reduced NO production are associated with PE. The aim of this study was to clarify the role on hepatic function by excess sFlt1 in the absence of eNOS gene product. We first overexpressed sFlt1 using adenovirus in eNOS^−/− and eNOS^+/+ mice. Excessive sFlt1 and lack of eNOS synergistically increased plasma levels of liver transaminases, exacerbated infiltration of inflammatory cells, elevated expression levels of cytokines in the liver, and aggravated oxidative stress and coagulation abnormalities. Lack of eNOS in the presence of excess sFlt1 also induced thrombocytopenia, whereas eNOS^+/+ mice with excess sFlt1 alone showed no or modest liver phenotype. Taken together, excessive sFlt1 and lack of eNOS synergistically induce hepatic dysfunction and thrombocytopenia, suggesting a novel role for VEGF and nitric oxide signaling in hepatocyte-endothelial cross-talk in health and in liver injury states.

Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, mediates wound healing and inflammatory responses, exerting an effect on liver fibrosis and angiogenesis; however, the precise mechanism remains unclear. The aims of this study are to identify the role of PlGF in liver inflammation and fibrosis induced by bile duct ligation (BDL) in mice and to reveal the underlying molecular mechanism. PlGF small interfering RNA (siRNA) or non-targeting control siRNA was injected by tail vein starting 2 days after BDL. Liver inflammation, fibrosis, angiogenesis, macrophage infiltration, and hepatic stellate cells (HSCs) activation were examined. Our results showed that PlGF was highly expressed in fibrotic livers and mainly distributed in activated HSCs and macrophages. Furthermore, PlGF silencing strongly reduced the severity of liver inflammation and fibrosis, and inhibited the activation of HSCs. Remarkably, PlGF silencing also attenuated BDL-induced hepatic angiogenesis, as evidenced by attenuated liver endothelial cell markers CD31 and von Willebrand factor immunostaining and genes or protein expression. Interestingly, these pathological ameliorations by PlGF silencing were due to a marked reduction in the numbers of intrahepatic F4/80⁺, CD68⁺, and Ly6C⁺ cell populations, which were reflected by a lower expression of these macrophage marker molecules in fibrotic livers. In addition, knockdown of PlGF by siRNA inhibited macrophages activation and substantially suppressed the expression of pro-inflammatory cytokines and chemokines in fibrotic livers. Mechanistically, evaluation of cultured RAW 264.7 cells revealed that VEGF receptor 1 (VEGFR1) mainly involved in mediating the role of PlGF in macrophages recruitment and activation, since using VEGFR1 neutralizing antibody blocking PlGF/VEGFR1 signaling axis significantly inhibited macrophages migration and inflammatory responses. Together, these findings indicate that PlGF plays an important role in liver inflammation, angiogenesis, and fibrosis by promoting hepatic macrophage recruitment and activation, and suggest that blockage of PlGF could be a promising novel therapy for chronic fibrotic liver diseases.

• Kupffer cells
• angiogenesis
• hepatic fibrosis
• hepatic stellate cells
• inflammation
• macrophage
• placental growth factor
• small interfering RNA

• ANGIOGENESIS
• PORTAL HYPERTENSION

• angiogenesis
• farnesoid X receptor
• hepatic venous pressure gradient
• nitric oxide
• non-selective β-blockers
• portal hypertension
• renin–angiotensin–aldosterone
• statins

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family and is involved in pathological angiogenesis associated with chronic liver diseases. However, the precise mechanisms underlying PlGF signalling contributing to liver fibrosis and angiogenesis remain largely unexplored. This study aimed to assess the effect of reducing PlGF expression using small interfering RNA (siRNA) on experimental liver fibrosis and angiogenesis, and to elucidate the underlying molecular mechanisms. Fibrosis was induced in mice by carbon tetrachloride (CCl₄) for 8 weeks, and mice were treated with PlGF siRNA or non‐targeting control siRNA starting two weeks after initiating CCl₄ injections. The results showed that PlGF was highly expressed in cirrhotic human and mice livers; which mainly distributed in activated hepatic stellate cells (HSCs). PlGF silencing robustly reduced liver inflammation, fibrosis, intrahepatic macrophage recruitment, and inhibited the activation of HSCs in vivo. Moreover, PlGF siRNA‐treated fibrotic mice showed diminished hepatic microvessel density and angiogenic factors, such as hypoxia‐inducible factor‐1α (HIF‐1α), VEGF and VEGF receptor‐1. Moreover, down‐regulation of PlGF with siRNA in HSCs inhibited the activation and proliferation of HSCs. Mechanistically, overexpression of PlGF in activated HSCs was induced by hypoxia dependent on HIF‐1α, and PlGF induces HSC activation and proliferation via activation the phosphatidylinositol 3‐kinase (PI3K)/Akt signalling pathways. These findings indicate that PlGF plays an important role in liver fibrosis‐associated angiogenesis and that blockage of PlGF could be an effective strategy for chronic liver disease.

• angiogenesis
• cirrhosis
• hepatic fibrosis
• hepatic stellate cells
• placental growth factor
• small interfering RNA

Latest data suggest that placental growth factor (PLGF), growth differentiation factor-15 (GDF-15) and hepatic growth factor (HGF) are involved in hepatic fibrogenesis. Diagnostic performance of these markers for non-invasive liver fibrosis prediction was evaluated based on liver histology and stiffness. In total 834 patients were recruited. Receiver-operating-characteristics were used to define cut-offs for markers correlating to fibrosis stages. Odds-ratios were calculated for the presence/absence of fibrosis/cirrhosis and confirmed in the sub-group of patients phenotyped by elastography only. Logistic and uni- and multivariate regression analyses were used to test for association of markers with liver fibrosis stages and for independent prediction of liver histology and stiffness. Marker concentrations correlated significantly (P<0.001) with histology and stiffness. Cut-offs for liver fibrosis (≥F2) were PLGF = 20.20 pg/ml, GDF15 = 1582.76 pg/ml and HGF = 2598.00 pg/ml. Logistic regression confirmed an increase of ORs from 3.6 over 33.0 to 108.4 with incremental (1–3) markers positive for increased liver stiffness (≥12.8kPa; all P<0.05). Subgroup analysis revealed associations with advanced fibrosis for HCV (three markers positive: OR = 59.9, CI 23.4–153.4, P<0.001) and non-HCV patients (three markers positive: OR = 144, CI 59–3383, P<0.001). Overall, serum markers identified additional 50% of patients at risk for advanced fibrosis presenting with low elastography results. In conclusion, this novel combination of markers reflects the presence of significant liver fibrosis detected by elastography and histology and may also identify patients at risk presenting with low elastography values.

• Hepatocellular carcinoma (HCC)
• acute liver failure
• lactate dehydrogenase (LDH)
• sorafenib

Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)–hypoxia-inducible factor-1α (HIF-1α)–vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK–HIF-1α–VEGF signaling pathway.

• Angiogenesis
• Celecoxib
• Hepatic arterioportal fistulas
• Liver cirrhosis
• Octreotide
• Portal hypertension

• endoplasmic reticulum stress
• fibrosis
• liver cirrhosis
• myofibroblast
• scleroderma

• Animals
• Cells, Cultured
• Endoplasmic Reticulum Stress
• Endoribonucleases/metabolism
• Fibrosis/pathology
• Humans
• Liver/pathology
• Mice
• MicroRNAs/metabolism
• Protein Serine-Threonine Kinases/metabolism
• Skin/pathology
• Unfolded Protein Response
• X-Box Binding Protein 1/metabolism

• aflibercept
• choroidal neovascularization
• ranibizumab
• spectral domain-optical coherence tomography

• PGF
• cerebral vessels
• circle of Willis
• fetal development
• pre-eclampsia
• stroke

• Animals
• Brain/blood supply
• Brain/metabolism
• Brain/pathology
• Brain Ischemia/genetics
• Brain Ischemia/metabolism
• Brain Ischemia/pathology
• Carotid Artery, Common/metabolism
• Carotid Artery, Common/pathology
• Coronary Stenosis/genetics
• Coronary Stenosis/metabolism
• Coronary Stenosis/pathology
• Disease Models, Animal
• Embryo, Mammalian
• Female
• Fetus
• Gene Expression Regulation
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neovascularization, Pathologic/genetics
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Placenta Growth Factor
• Pre-Eclampsia/genetics
• Pre-Eclampsia/metabolism
• Pre-Eclampsia/pathology
• Pregnancy
• Pregnancy Proteins/deficiency
• Pregnancy Proteins/genetics
• Signal Transduction
• Vascular Endothelial Growth Factor A/genetics
• Vascular Endothelial Growth Factor A/metabolism
• Vascular Endothelial Growth Factor Receptor-1/genetics
• Vascular Endothelial Growth Factor Receptor-1/metabolism
• Vascular Endothelial Growth Factor Receptor-2/genetics
• Vascular Endothelial Growth Factor Receptor-2/metabolism

• Canadian Institutes of Health Research

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. We previously showed that the inhibition of placental growth factor (PlGF) exerts antitumour effects and induces vessel normalisation, possibly reducing hypoxia. However, the exact mechanism underlying these effects remains unclear. Because hypoxia and endoplasmic reticulum stress, which activates the unfolded protein response (UPR), have been implicated in HCC progression, we assessed the interactions between PlGF and these microenvironmental stresses.

PlGF knockout mice and validated monoclonal anti-PlGF antibodies were used in a diethylnitrosamine-induced mouse model for HCC. We examined the interactions among hypoxia, UPR activation and PlGF induction in HCC cells.

Both the genetic and pharmacological inhibitions of PlGF reduced the chaperone levels and the activation of the PKR-like endoplasmic reticulum kinase (PERK) pathway of the UPR in diethylnitrosamine-induced HCC. Furthermore, we identified that tumour hypoxia was attenuated, as shown by reduced pimonidazole binding. Interestingly, hypoxic exposure markedly activated the PERK pathway in HCC cells in vitro, suggesting that PlGF inhibition may diminish PERK activation by improving oxygen delivery. We also found that PlGF expression is upregulated by different chemical UPR inducers via activation of the inositol-requiring enzyme 1 pathway in HCC cells.

PlGF inhibition attenuates PERK activation, likely by tempering hypoxia in HCC via vessel normalisation. The UPR, in turn, is able to regulate PlGF expression, suggesting the existence of a feedback mechanism for hypoxia-mediated UPR that promotes the expression of the angiogenic factor PlGF. These findings have important implications for our understanding of the effect of therapies normalising tumour vasculature.

The online version of this article (doi:10.1186/s12885-015-1990-6) contains supplementary material, which is available to authorized users.