Circulating Maternal sFLT1 (Soluble fms-Like Tyrosine Kinase-1) Is Sufficient to Impair Spiral Arterial Remodeling in a Preeclampsia Mouse Model.

[Figure: see text].

MicroRNAs and the HIF/VEGF axis in ocular neovascular diseases.

Ocular neovascular diseases, such as proliferative diabetic retinopathy, retinopathy of prematurity and neovascular age-related macular degeneration, are the leading causes of visual impairment worldwide. The hypoxia-inducible factors and vascular endothelial growth factors are key molecular promoters of ocular neovascularization. Moreover, the role of microRNAs as regulators of angiogenesis has been expanding, particularly hypoxia-associated microRNA; hypoxamiRs. This review provides a summary of hypoxamiRs that directly and specifically target HIF1A and VEGF mRNAs, thus critically involved in the regulation of ocular neovascular pathologies. The discussed microRNAs highlight putative diagnostic markers and therapeutic agents in choroidal and retinal angiogenic diseases, including proliferative diabetic retinopathy, retinopathy of prematurity and neovascular age-related macular degeneration.

HIF-1/AKT Signaling-Activated PFKFB2 Alleviates Cardiac Dysfunction and Cardiomyocyte Apoptosis in Response to Hypoxia.

Myocardial infarction (MI) is the most prevalent disease with severe mortality, and hypoxia-induced cardiac injury and cardiomyocyte apoptosis are the significant and harmful consequences of this disease. The cross talk between hypoxia signaling and glycolysis energy flux plays a critical role in modulating MI-related heart disorder. However, the underlying mechanism remains unclear. Here, we aimed to explore the effect of a key glycolytic enzyme of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 2 (PFKFB2) on cardiac dysfunction and apoptosis in response to hypoxia. Our data demonstrated that the mRNA and protein expression of PFKFB2 were significantly elevated in the MI mice. The MI treatment promoted the activation of PFKFB2 in vivo, as presented by the remarkably increased phosphorylation levels of PFKFB2. PFKFB2 depletion enhanced MI-induced cardiac dysfunction and cardiomyocyte apoptosis in the MI mouse model. Moreover, hypoxia treatment dramatically upregulated the expression and activation of PFKFB2 in a time-dependent manner in cardiomyocytes. Hypoxia-stimulated PFKFB2 relieved hypoxia-induced cardiomyocyte apoptosis in vitro. PFKFB2 activated the fructose-2, 6-bisphosphate (Fru-2, 6-p2) /PFK/anaerobic adenosine triphosphate (ATP) glycolysis energy flux in response to hypoxia in cardiomyocytes. Mechanically, hypoxia-activated PFKFB2 by stimulating the hypoxia-inducible factor 1 (HIF-1) /ATK signaling. Thus, we conclude that HIF-1/AKT axis-activated PFKFB2 alleviates cardiac dysfunction and cardiomyocyte apoptosis in response to hypoxia. Our finding presents a new insight into the mechanism by which HIF-1/AKT/PFKFB2 signaling modulates MI-related heart disorder under the hypoxia condition, providing potential therapeutic targets and strategy for hypoxia-related myocardial injury.

Mechanisms and treatment of bone pain in multiple myeloma.

PURPOSE OF REVIEW: Multiple myeloma is a haematological malignancy of differentiated B lymphocytes, known as plasma cells. The disease is common in the UK (incidence of 9 cases per 100 000 people) and the most frequent presentation is bone pain caused by skeletal damage. Patients with myeloma also experience neuropathic pain induced by chemotherapy. The management of pain in multiple myeloma is frequently demanding and often sub-optimally addressed. This review seeks to summarize a rational approach to the management of pain experienced by multiple myeloma patients. RECENT FINDINGS: Bone pain has a dramatic detrimental impact on a patient's physical capacity, and therefore, quality of life. Various mechanisms of bone pain have been elucidated; however, neuropathic bone pain in multiple myeloma is not completely understood. Potential mechanisms for this phenomenon; namely increased intraosseous pressure and the acidity of the bone marrow in the disease state will be interrogated. The current analgesic pathways used to treat multiple myeloma bone pain and new advances in therapies that may confer future benefit to patients will briefly be reviewed. SUMMARY: Holistic care and the provision of an array of pain relief methods is required to achieve effective pain control in multiple myeloma bone pain and requires a concerted effort from the healthcare team to be realized.

The Activin Receptor, Activin-Like Kinase 4, Mediates Toxoplasma Gondii Activation of Hypoxia Inducible Factor-1.

To grow and cause disease, intracellular pathogens modulate host cell processes. Identifying these processes as well as the mechanisms used by the pathogens to manipulate them is important for the development of more effective therapeutics. As an example, the intracellular parasite Toxoplasma gondii induces a wide variety of changes to its host cell, including altered membrane trafficking, cytoskeletal reorganization, and differential gene expression. Although several parasite molecules and their host targets have been identified that mediate- these changes, few are known to be required for parasite replication. One exception is the host cell transcription factor, hypoxia-inducible factor-1 (HIF-1), which is required for parasite replication in an oxygen-dependent manner. Toxoplasma activates HIF-1 by stabilizing the HIF-1α subunit, and this is dependent on the signaling from the Activin-Like Kinase (ALK) receptor superfamily. Here, we demonstrate that specific overexpression of the ALK family member, ALK4, increased HIF-1 activity in Toxoplasma-infected cells, and this increase required ALK4 kinase activity. Moreover, Toxoplasma stimulated ALK4 to dimerize with its co-receptor, ActRII, and also increased ALK4 kinase activity, thereby demonstrating that Toxoplasma activates the ALK4 receptor. ALK4 activation of HIF-1 was independent of canonical SMAD signaling but rather was dependent on the non-canonical Rho GTPase and JNK MAP kinase signaling pathways. Finally, Toxoplasma increased rates of ALK4 ubiquitination and turnover. These data provide the first evidence indicating that ALK4 signaling is a target for a microbial pathogen to manipulate its host cell.

mTORC1 and mTORC2 Expression Levels in Oral Squamous Cell Carcinoma: An Immunohistochemical and Clinicopathological Study.

BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) plays a critical role in the regulation of tumor cell motility, invasion and cancer cell metastasis. mTOR consists of two separate multi-protein complexes, mTOR complex (mTORC) 1 and mTORC2. MATERIALS AND METHODS: We investigated the expression levels of mTORC1 and mTORC2 immunohistochemically in oral squamous cell carcinoma (OSCC). RESULTS: mTORC1 and mTORC2 were more highly expressed in tumors than in normal oral mucosa. mTORC1 expression was correlated with T classification, N classification, and survival rate (p<0.05), whereas mTORC2 expression was only correlated with T classification (p<0.05). Histologically, the expression levels of mTORC1 and mTORC2 correlated with cancer cell invasion and the expression of proliferating cell nuclear antigen (p<0.05), respectively. Expression levels of vascular endothelial growth factors and hypoxia-inducible factor 1 in the mTORC1 (-)/ mTORC2 (+) group were significantly lower than those in other groups. CONCLUSION: These findings suggested that mTORC1 and mTORC2 could be promising anti-tumor targets in OSCC, and mTORC1 (-)/mTORC2 (+) may have a correlation with the malignant potential of OSCC.

Hypoxia and HIF-1 activation in bacterial infections.

For most of the living beings, oxygen is one of the essential elements required to sustain life. Deprivation of oxygen causes tissue hypoxia and this severely affects host cell and organ functions. Tissue hypoxia is a prominent microenvironmental condition occurring in infections and there is a body of evidence that hypoxia and inflammation are interconnected with each other. The primary key factor mediating the mammalian hypoxic response is hypoxia inducible factor (HIF)-1, which regulates oxygen homeostasis on cellular, tissue and organism level. Recent studies show that HIF-1 plays a central role in angiogenesis, cancer and cardiovascular disease but also in bacterial infections. Activation of HIF-1 depends on the nature of the pathogen and the characteristics of infections in certain hosts. Up to date, it is not completely clear whether the phenomenon of HIF-1 activation in infections has a protective or detrimental effect on the host. In this review, we give an overview of whether and how hypoxia and HIF-1 affect the course of infections.

Hypoxia-inducible factor-1 expression predicts osteosarcoma patients' survival: a meta-analysis.

Osteosarcoma, the most common primary bone malignancy, is characterized by easily relapsing and metastasizing. Hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumorigenesis, affecting tumor metabolism, differentiation, angiogenesis, proliferation and metastasis, and has been found to be associated with survival in patients with osteosarcoma. The possible prognostic value of HIF-1 was investigated in many studies, but the results were inconsistent. We therefore conducted a meta-analysis to elucidate the correlation of HIF-1 expression, analyzed by immunohistochemistry in osteosarcoma tissues, with prognosis. The association degree was assessed by calculation of the hazard ratio (HR) and risk ratio (RR) with corresponding 95% confidence intervals (CIs). Follow-up information was available for 486 patients from 7 studies. The results showed that high HIF-1 expression was associated with a worse prognosis when compared to low or undetectable HIF-1 expression, with an HR of 3.67 (95% CI 2.24-5.99; p<0.001) for overall survival (OS) and an RR of 3.72 (95% CI 2.26-6.13; p<0.001) for OS. The RR of 2.55 for disease-free survival (DFS) did not show any obvious relationship between a high level of HIF-1 and DFS (95% CI 0.95-6.87; p = 0.064). The stability of this result was tested by sensitivity analysis and no significant change was detected. This meta-analysis suggests that HIF-1 is an effective prognostic biomarker to predict OS in patients with osteosarcoma.

Disrupted intestinal structure in a rat model of intermittent hypoxia.

Obstructive sleep apnea (OSA) is a chronic condition characterized by chronic intermittent hypoxia (IH) and subsequent reoxygenation (ROX). The gastrointestinal system, which is particularly sensitive to tissue hypoxia and reduced perfusion, is likely to be affected by OSA. A rat model of IH was used to analyze oxidative stress-associated genes and tight junction proteins by reverse transcription­quantitative polymerase chain reaction. Subsequently, altered morphology of the duodenal mucosa and elevated Chiu scores were observed in the IH­exposed rats. In addition, IH exposure resulted in upregulation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, NADPH oxidase 2 and p22phox, in the small intestine, and upregulation of transcription factors, including hypoxia­inducible factor-1, nuclear factor­κB and activator protein-1. Furthermore, the mRNA expression levels of intestinal tight junction (TJ)-related proteins, claudin-1 and claudin-4, were decreased in the IH­exposed group, as compared with in the control group. In conclusion, the present study demonstrated that OSA, which is characterized by IH and ROX, may lead to disruption of the duodenum. The mechanism underlying the effects of OSA on duodenal morphology may be associated with increased oxidative stress and activation of transcription factors, subsequently inducing intestinal TJ disruption and intestinal injury.

Biological outcome and mapping of total factor cascades in response to HIF induction during regenerative angiogenesis.

Hypoxia Inducible Factor (HIF) is the main transcription factor that mediates cell response to hypoxia. Howeverthe complex factor cascades induced by HIF during regenerative angiogenesis are currently incompletely mapped and the biological outcome mediated by chronic HIF induction during vessel regeneration are not well known. Here, we investigated the biological impact of HIF induction on vascular regeneration and identified the differentially regulated genes during regeneration, HIF induction and hypoxic regeneration. The use of the fin zebrafish regeneration model revealed that exposure to HIF inducer (cobalt chloride) prevents vessel differentiation by maintaining their vascular plexuses in an immature state. The regenerated fins are easily breakable, lacking completely endochondral ossification. Gene expression arrays combined to gene functional enrichment analysis revealed that regenerative process and HIF induction shared the regulation of common genes mainly involved in DNA replication and proteasome complex. HIF induction during regeneration affected the expression of exclusive genes involved in cell differentiation and communication, consistent with the observed immature vascular plexuses of the regenerated fins during HIF induction. The use of morpholino (MO) knockdown strategy revealed that the expression of some of these genes such as tubulin and col10a1 are required for fin regeneration. Taken together, this study revealed the impact of HIF induction on regenerative angiogenesis and provided a framework to develop a gene network leading to regenerative process during HIF expression.

Cisplatin treatment increases stemness through upregulation of hypoxia-inducible factors by interleukin-6 in non-small cell lung cancer.

Cisplatin-resistant A549 and H157 (A549CisR and H157CisR) non-small cell lung cancer cells show increased stemness of cancer stem cells (CSCs) compared to their parental cells. We investigated whether interleukin-6 (IL-6) signaling contributes to this increased stemness in cisplatin-resistant cells. When A549CisR and H157CisR cells were treated with neutralizing IL-6 antibody, decreased cisplatin resistance was observed, whereas IL-6 treatment of parental cells resulted in increased cisplatin resistance. Expression of the CSC markers was significantly upregulated in IL-6-expressing scramble cells (in vitro) and scramble cell-derived tumor tissues (in vivo) after cisplatin treatment, but not in IL-6 knocked down (IL-6si) (in vitro) cells and in IL-6si cell-derived tumor tissues (in vivo), suggesting the importance of IL-6 signaling in triggering increased stemness during cisplatin resistance development. Hypoxia inducible factors (HIFs) were upregulated by IL-6 and responsible for the increased CSC stemness on cisplatin treatment. Mechanism dissection studies found that upregulation of HIFs by IL-6 was through transcriptional control and inhibition of HIF degradation. Treatment of HIF inhibitor (FM19G11) abolished the upregulation of CSC markers and increased sphere formations in IL-6 expressing cells on cisplatin treatment. In all, IL-6-mediated HIF upregulation is important in increasing stemness during cisplatin resistance development, and we suggest that the strategies of inhibiting IL-6 signaling or its downstream HIF molecules can be used as future therapeutic approaches to target CSCs after cisplatin treatment for lung cancer.

Mimosine suppresses the PGF2α-induced synthesis of osteoprotegerin but not interleukin-6 in osteoblasts.

Mimosine, a plant amino acid, is known to act as a normoxic inducer of hypoxia-inducible factor (HIF). Previous research has suggested that HIF plays important roles in angiogenesis-osteogenesis coupling and bone metabolism. We previously reported that prostaglandin F2α (PGF2α) induced osteoprotegerin synthesis through p38 mitogen-activated protein (MAP) kinase, p44/p42 MAP kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. We have also demonstrated that PGF2α induced the synthesis of interleukin-6 (IL-6) via p38 MAP kinase and p44/p42 MAP kinase but not SAPK/JNK in these cells. In the present study, we investigated the effects of mimosine on the PGF2α-induced synthesis of osteoprotegerin or IL-6 in MC3T3-E1 cells. We found that deferoxamine, another inducer of HIF, as well as mimosine, upregulated the protein levels of HIF-1α. Both mimosine and deferoxamine significantly suppressed the PGF2α-induced release of osteoprotegerin, and the mRNA expression level, without markedly affecting PGF2α-induced IL-6 release. Both mimosine and deferoxamine, by themselves, induced the release of vascular endothelial growth factor. The phosphorylation of p38 MAP kinase, p44/p42 MAP kinase or SAPK/JNK induced by PGF2α was not markedly affected by either mimosine or deferoxamine. Thus, the results of the present study strongly suggest that mimosine, a normoxic inducer of HIF, inhibits the PGF2α­induced osteoprotegerin synthesis without affecting the IL-6 synthesis in osteoblasts.

α-Solanine inhibits vascular endothelial growth factor expression by down-regulating the ERK1/2-HIF-1α and STAT3 signaling pathways.

In tumors, vascular endothelial growth factor (VEGF) contributes to angiogenesis, vascular permeability, and tumorigenesis. In our previous study, we found that α-solanine, which is widespread in solanaceae, has a strong anti-cancer effect under normoxia. However, it is unknown whether α-solanine has a similar effect under hypoxia. We used cobalt chloride (CoCl2) to mimic hypoxia in vitro. HIF-1α, which is almost undetectable under normoxia, was significantly increased. Simultaneously, another regulator of VEGF, STAT3, was also significantly activated by CoCl2. We utilized α-solanine in co-culture with CoCl2. α-solanine decreased the expression of VEGF and loss of E-cadherin. α-solanine also suppressed the activation of phospho-ERK1/2 (p-ERK1/2), HIF-1α, and STAT3 signaling. The results provide new evidence that α-solanine has a strong anti-cancer effect via the ERK1/2-HIF-1α and STAT3 signaling pathways and suggest that it may be a potential new drug.

Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function.

Interactions between the microbiota and distal gut are fundamental determinants of human health. Such interactions are concentrated at the colonic mucosa and provide energy for the host epithelium through the production of the short-chain fatty acid butyrate. We sought to determine the role of epithelial butyrate metabolism in establishing the austere oxygenation profile of the distal gut. Bacteria-derived butyrate affects epithelial O2 consumption and results in stabilization of hypoxia-inducible factor (HIF), a transcription factor coordinating barrier protection. Antibiotic-mediated depletion of the microbiota reduces colonic butyrate and HIF expression, both of which are restored by butyrate supplementation. Additionally, germ-free mice exhibit diminished retention of O2-sensitive dyes and decreased stabilized HIF. Furthermore, the influences of butyrate are lost in cells lacking HIF, thus linking butyrate metabolism to stabilized HIF and barrier function. This work highlights a mechanism where host-microbe interactions augment barrier function in the distal gut.

1α,25-Dihydroxyvitamin D3 upregulates HIF-1 and TREM-1 via mTOR signaling.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is induced by 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) in human monocytes/macrophages and epithelial cells. However, little information is available regarding the mechanism of 1,25(OH)2D3-induced TREM-1 expression in human monocytes/macrophages. In this study, 1,25(OH)2D3 was shown to strongly upregulate hypoxia-inducible transcription factor (HIF) in PMA-differentiated U937 cells. However, HIF was not mainly involved in 1,25(OH)2D3-induced TREM-1 expression. Instead, 1,25(OH)2D3-induced expression of TREM-1 was inhibited by rapamycin, a specific inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, indicating the involvement of mTOR. Induction of HIF proteins by 1,25(OH)2D3 was also inhibited by rapamycin. In addition, 1,25(OH)2D3 induced the phosphorylation of p70S6 kinase, a target of mTOR complex 1 (mTORC1). Our results suggest that 1,25(OH)2D3 induces the expression of TREM-1 through the mTOR signaling pathway in human macrophages.

The role of hypoxia inducible factor-1 in hepatocellular carcinoma.

Hypoxia is a common feature of many solid tumors, including hepatocellular carcinoma (HCC). Hypoxia can promote tumor progression and induce radiation and chemotherapy resistance. As one of the major mediators of hypoxic response, hypoxia inducible factor-1 (HIF-1) has been shown to activate hypoxia-responsive genes, which are involved in multiple aspects of tumorigenesis and cancer progression, including proliferation, metabolism, angiogenesis, invasion, metastasis and therapy resistance. It has been demonstrated that a high level of HIF-1 in the HCC microenvironment leads to enhanced proliferation and survival of HCC cells. Accordingly, overexpression, of HIF-1 is associated with poor prognosis in HCC. In this review, we described the mechanism by which HIF-1 is regulated and how HIF-1 mediates the biological effects of hypoxia in tissues. We also summarized the latest findings concerning the role of HIF-1 in the development of HCC, which could shed light on new therapeutic approaches for the treatment of HCC.

The expression of succinate dehydrogenase in breast phyllodes tumor.

The purpose of this study is to investigate the expression of succinate dehydrogenase (SDH)A, SDHB, and HIF-1α in phyllodes tumors and the association with clinic-pathologic factors. Using tissue microarray (TMA) for 206 phyllodes tumor cases, we performed immunohistochemical stains for SDHA, SDHB, and HIF-1α and analyzed their expression in regard to clinicopathologic parameters of each case. The cases were comprised of 156 benign, 34 borderline, and 16 malignant phyllodes tumors. The expression of stromal SDHA and epithelial- and stromal- SDHB increased as the tumor progressed from benign to malignant (P⟨0.001). There were five stromal SDHA-negative cases and 31 stromal SDHB-negative cases. SDHB negativity was associated with a lower histologic grade (P=0.054) and lower stromal atypia (P=0.048). Univariate analysis revealed that a shorter disease free survival (DFS) was associated with stromal SDHB high-positivity (P=0.013) and a shorter overall survival (OS) was associated with high-positivity of stromal SDHA and SDHB (P⟨0.001 and P⟨0.001, respectively). The multivariate Cox analysis with the variables stromal cellularity, stromal atypia, stromal mitosis, stromal overgrowth, tumor margin, stromal SDHA expression, and stromal SDHB expression revealed that stromal overgrowth was associated with a shorter DFS (hazard ratio: 24.78, 95% CI: 3.126-196.5, P=0.002) and a shorter OS (hazard ratio: 176.7, 95% CI: 8.466-3691, P=0.001). In conclusion, Tumor grade is positively correlated with SDHA and SDHB expression in the tumor stroma in phyllodes tumors of the breast. This result may be attributed to the increased metabolic demand in high grade tumors.

Alterations of pancreatic islet structure, metabolism and gene expression in diet-induced obese C57BL/6J mice.

The reduction of functional ß cell mass is a key feature of type 2 diabetes. Here, we studied metabolic functions and islet gene expression profiles of C57BL/6J mice with naturally occurring nicotinamide nucleotide transhydrogenase (NNT) deletion mutation, a widely used model of diet-induced obesity and diabetes. On high fat diet (HF), the mice developed obesity and hyperinsulinemia, while blood glucose levels were only mildly elevated indicating a substantial capacity to compensate for insulin resistance. The basal serum insulin levels were elevated in HF mice, but insulin secretion in response to glucose load was significantly blunted. Hyperinsulinemia in HF fed mice was associated with an increase in islet mass and size along with higher BrdU incorporation to ß cells. The temporal profiles of glucose-stimulated insulin secretion (GSIS) of isolated islets were comparable in HF and normal chow fed mice. Islets isolated from HF fed mice had elevated basal oxygen consumption per islet but failed to increase oxygen consumption further in response to glucose or carbonyl cyanide-4-trifluoromethoxyphenylhydrazone (FCCP). To obtain an unbiased assessment of metabolic pathways in islets, we performed microarray analysis comparing gene expression in islets from HF to normal chow-fed mice. A few genes, for example, those genes involved in the protection against oxidative stress (hypoxia upregulated protein 1) and Pgc1α were up-regulated in HF islets. In contrast, several genes in extracellular matrix and other pathways were suppressed in HF islets. These results indicate that islets from C57BL/6J mice with NNT deletion mutation develop structural, metabolic and gene expression features consistent with compensation and decompensation in response to HF diet.

Extensive podocyte loss triggers a rapid parietal epithelial cell response.

Damage to podocytes is a central pathomechanism of proteinuric kidney disease. However, it is not fully understood how podocyte injury evolves to progressive glomerulopathies such as FSGS or collapsing glomerulopathy. In particular, the role of parietal epithelial cells remains controversial. Here, we show that adriamycin induces DNA damage and podocyte lysis in mice without evidence of autophagy, endoplasmic reticulum stress, or necroptosis. After extensive podocyte loss, activated parietal cells mediated tuft re-epithelialization by two distinct mechanisms. In the majority of glomeruli, vacuolized parietal epithelial cells attached to denuded glomerular basement membrane and, occasionally, disengaged from the parietal basement membrane. Less frequently, parietal epithelial cells covered the denuded visceral basement membrane via formation of proliferative pseudocrescents. Notably, "visceralized" parietal epithelial cells did not express vascular endothelial growth factor but upregulated hypoxia-inducible factor 1 expression. The presence of visceralized parietal epithelial cells in sclerosing and collapsing lesions in a kidney biopsy from a patient with diabetes underscores the human relevance of our findings. In conclusion, repopulation of the glomerular tuft by parietal cells may represent a compensatory response to extensive podocyte loss. Our results suggest, however, that visceralized parietal epithelial cells cannot induce revascularization of the hyalinized tuft, resulting in hypoxic cell death and irreversible destruction of the glomerulus.

Decorin inhibits angiogenic potential of choroid-retinal endothelial cells by downregulating hypoxia-induced Met, Rac1, HIF-1α and VEGF expression in cocultured retinal pigment epithelial cells.

Choroidal neovascularization (CNV) is one of the most common causes of severe vision loss. Decorin, a multiple receptor tyrosine kinase inhibitor, has been recently shown to play an important regulatory role in angiogenic response. This study aims to investigate whether the overexpression of decorin in retinal pigment epithelial (RPE) cells under hypoxia alters the in vitro angiogenic ability of cocultured choroid-retinal endothelial cells and to explore the possible mechanisms involved. Human RPE cells (ARPE-19) were subjected to hypoxia with or without decorin pretreatment, and RNA interference technique was used to knock down the Met gene in ARPE-19 cells. Cell viability was determined using the Cell Counting Kit-8 assay. Expression of Met, Rac1 and hypoxia-inducible factor-1 alpha (HIF-1α) was evaluated by western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Vascular endothelial growth factor (VEGF) expression was evaluated by enzyme-linked immunosorbent assay (ELISA) and qRT-PCR. We then constructed a recombinant lentiviral vector carrying the decorin gene to transduce ARPE-19 cells. The overexpression of decorin in transduced RPE cells was confirmed by qRT-PCR and western blot. The transduced RPE cells were then cocultured with rhesus macaque choroid-retinal endothelial cells (RF/6A) in a transwell coculture system to observe the effects of decorin overexpression in ARPE-19 cells on the proliferation, migration and tube formation of RF/6A cells. In response to hypoxia, the VEGF concentrations in the culture supernatants increased greatly at 24 and 48 h, and this effect was inhibited significantly and nearly equally in the presence of 50-200 nM decorin. Decorin pretreatment before hypoxia exposure effectively reduced the hypoxia-induced expression of Met, Rac1, HIF-1α and VEGF in ARPE-19 cells. Transfection of small interfering RNA against Met to ARPE-19 cells also resulted in significant downregulation of Rac1, HIF-1α and VEGF under hypoxia, and this effect was similar to that noted with decorin pretreatment alone or with their combination. Results from the coculture system showed that the overexpression of decorin in ARPE-19 cells significantly inhibited the proliferation, migration and tube formation of RF/6A cells. These results indicate that Met pathway activation plays an important role in the upregulation of VEGF in RPE cells under hypoxia. Decorin may interfere with angiogenesis by downregulating hypoxia-induced Met, Rac1, HIF-1α and VEGF expression in RPE cells, which suggests a potential strategy for the inhibition of CNV.