Receptor activator of nuclear factor (NF)–κB ligand (RANKL) increases vascular permeability: impaired permeability and angiogenesis in eNOS-deficient mice

Kim, Jung Min; Cho, Young-Lai; Choi, Jaehoon; Kim, Yong‐Hak; Kim, Jeong Hun; Yu, Young Suk; Rho, Jaerang; Mochizuki, Naoki; Kim, Young‐Myeong; Oh, Goo Taeg; Kwon, Young-Guen

doi:10.1182/blood-2006-06-029298

Cited by 98 publications

(71 citation statements)

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“…[18][19][20][21][22][23][24][25][26][27][28] Accumulating evidence also suggests that chronic subclinical inflammation has an important role in the pathogenesis of DR. An early event in the pathogenesis of diabetic vasculopathy is leukocyte adherence to retinal vascular endothelium, resulting in EC death, vascular leakage, and capillary closure. 18 Clinical evidence indicates that DMO results from breakdown of the inner blood-retinal barrier, 96 which is maintained by EC TJ complexes.…”

Section: Scientific Basismentioning

confidence: 99%

“…104 Mukarami et al 105 and Felinski et al 101 have attempted to elucidate the mechanisms of VEGF enhancement of vascular permeability. Other factors including TNFα and interleukin (IL)-1B, 106 nuclear factor-κB (NF-κB) receptor activator, 21,22 hepatocyte growth factor (HGF), 23 and the accumulation of advanced glycation end products 20 are known to induce vascular leakage independent of VEGF-A. Adhesion molecules such as CD44 24,25 may also contribute significantly to microvascular occlusions and angiogenesis.…”

Section: Scientific Basismentioning

confidence: 99%

“…The contributions of the choroidal vasculature to the clinical disease of DR are less well understood, but again will be largely contributed to by the choroidal EC (CEC) alterations. [6][7][8][9] It is known that retinal vascular leakage in DMO is contributed to by vascular endothelial growth factor (VEGF) upregulation as well as non-VEGFdependent inflammatory pathways, so that chronic subclinical inflammation is important in the pathogenesis of DR. [18][19][20][21][22][23][24][25][26][27][28] An early event in the pathogenesis of diabetic vasculopathy is leukocyte adherence to retinal vascular endothelium, resulting in EC death, vascular leakage, and capillary closure 18 (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

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A review of therapies for diabetic macular oedema and rationale for combination therapy

Amoaku

Saker

Stewart

2015

Eye

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Diabetic macular oedema (DMO) is responsible for significant visual impairment in diabetic patients. The primary cause of DMO is fluid leakage resulting from increased vascular permeability through contributory anatomical and biochemical changes. These include endothelial cell (EC) death or dysfunction, pericyte loss or dysfunction, thickened basement membrane, loss or dysfunction of glial cells, and loss/change of EC Glycocalyx. The molecular changes include increased reactive oxygen species, pro-inflammatory changes: advanced glycation end products, intracellular adhesion molecule-1, Complement 5-9 deposition and cytokines, which result in increased paracellular permeability, tight junction disruption, and increased transcellular permeability. Laser photocoagulation has been the mainstay of treatment until recently when pharmacological treatments were introduced. The current treatments for DMO target reducing vascular leak in the macula once it has occurred, they do not attempt to treat the underlying pathology. These pharmacological treatments are aimed at antagonising vascular endothelial growth factor (VEGF) or non-VEGF inflammatory pathways, and include intravitreal injections of anti-VEGFs (ranibizumab, aflibercept or bevacizumab) or steroids (fluocinolone, dexamethasone or triamcinolone) as single therapies. The available evidence suggests that each individual treatment modality in DMO does not result in a completely dry macula in most cases. The ideal treatment for DMO should improve vision and improve morphological changes in the macular (eg, reduce macular oedema) for a significant duration, reduced adverse events, reduced treatment burden and costs, and be well tolerated by patients. This review evaluates the individual treatments available as monotherapies, and discusses the rationale and potential for combination therapy in DMO.

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Section: Scientific Basismentioning

confidence: 99%

Section: Scientific Basismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A review of therapies for diabetic macular oedema and rationale for combination therapy

Amoaku

Saker

Stewart

2015

Eye

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“…In addition to the known role of RANKL in the skeletal and immune systems (13), recent studies also reported a role of RANKL in angiogenesis. Certain authors support an inhibitory role of RANKL (14,15), whereas others showed a stimulating action on angiogenesis (16). Contrary to RANKL, VEGF is known as a potent mitogen angiogenic factor and is one of the most important molecules involved in the vascularization of bone tissue (17), thus its serum levels are considered an index of angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Bone metastases in gastric cancer follow a RANKL-independent mechanism

et al. 2013

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Abstract. Gastric cancer is one of the most common and lethal malignancies worldwide. Bone metastases in gastric cancer are less common than in other solid tumors, but when they occur the prognosis is generally poor. Increased osteoclastogenesis and osteoclast activity are common features in bone metastases caused by different osteotropic cancer. We investigated osteoclastogenesis and its mechanisms in gastric cancer by enrolling 31 newly diagnosed gastric cancer patients and 45 healthy controls. We studied in vitro osteoclastogenesis in the peripheral blood mononuclear cell cultures of patients and controls, showing spontaneous osteoclastogenesis for half of the patients. This osteoclastogenesis was RANKL-and TNF-α-independent. We analyzed primary tumor and bone metastatic tissues of gastric cancer for the expression of genes involved in osteoclastogenesis. The expression of transforming growth factor-β (TGF-β), osteoprotegerin (OPG), IL-7 and dickkopf-1 (DKK-1) was higher in primary tumors than in bone metastases. RANKL was not detectable in primary tumor or in bone metastatic tissue. The serum RANKL level was significantly higher in healthy controls than in patients, and it was not related to osteoclastogenesis, thereby suggesting that RANKL is not involved in the bone metastatic mechanisms in gastric cancer. We hypothesized a role of RANKL in angiogenesis, thus we compared the serum levels of RANKL to those of VEGF, since VEGF is directly related to angiogenesis. Different from RANKL, the VEGF serum levels were higher in gastric patients than in controls, suggesting a block of the angiogenesis inhibition due to RANKL. RANKL and VEGF serum levels were not predictive of overall survival in our cohort of gastric patients.

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“…7,8 We have also previously demonstrated additional vascular roles of RANKL in stimulating angiogenesis, expression of inflammatory adhesion molecules, and endothelial permeability. 9,10 Although RANKL has been emerging as a risk marker for cardiovascular disease, 11 the epidemiological data are still limited to ascertain clear association between RANKL level and cardiovascular disease. 6 Nevertheless, RANKL appears to be correlated with plaque destabilization and thrombosis based on its role in vascular calcium deposition and its prominent expression in advanced lesions.…”

mentioning

confidence: 99%

Receptor Activator of Nuclear Factor κB Ligand Is a Novel Inducer of Tissue Factor in Macrophages

Kim

Park

et al. 2010

Circulation Research

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Rationale: Although recent studies have suggested a role for the receptor activator of nuclear factor B ligand (RANKL) in the late stages of atherosclerosis (eg, plaque destabilization and rupture), the underlying mechanisms and subsequent events are unclear.Objective: Because blood clotting is common after plaque rupture, we hypothesized that RANKL influenced tissue factor (TF) expression and activity to initiate the coagulation cascade. Key Words: receptor activator of nuclear factor-B ligand Ⅲ tissue factor Ⅲ thrombosis Ⅲ atherosclerosis A therosclerosis is a well-studied chronic inflammatory disease that is characterized by thickening of the artery walls and formation of atherosclerotic plaques. 1 The later stage of atherosclerosis is accompanied by plaque destabilization and thrombus formation. 2 It is widely accepted that an abundance of active tissue factor (TF) in atherosclerotic plaques is a disastrous factor toward initiation and progression of atherothrombosis. 3,4 Hence, finding TF regulators seems to be of importance to advanced atherosclerosis and acute coronary syndrome. Methods and ResultsThe receptor activator of nuclear factor B ligand (RANKL) was initially identified as a regulator of bone remodeling. Recently, the physiological and pathological relevance of RANKL was extended to vascular biology, including atherosclerosis. 5 RANKL exists in either a cell-bound or a secreted form and it is produced by vascular cells and activated immune cells close to blood vessels. 6 RANKL is upregulated by inflammatory cytokines such as tumor necrosis factor-␣, interleukin-1␣, and interleukin-6. 3 The mRNA level of RANKL was increased in T cells in patients with unstable angina 7 and strong immunoreactivity of RANKL was detected in vulnerable plaques and thrombus from ruptured coronary lesions. 5 Several lines of evidence suggest that RANKL, its receptor (RANK) and osteoprotegerin are involved in atherosclerotic lesion progression and plaque destabilization and calcification. 7,8 We have also previously demonstrated additional vascular roles of RANKL in stimulating angiogenesis, expression of inflammatory adhesion molecules, and endothelial permeability. 9,10 Although RANKL has been emerging as a risk marker for cardiovascular disease, 11 the epidemiological data are still limited to ascertain clear association between RANKL level and cardiovascular disease. 6 Nevertheless, RANKL appears to be correlated with plaque destabilization and thrombosis based on its role in vascular calcium deposition and its prominent expression in advanced lesions. 5,7 In this study, we provide evidence for novel function of RANKL as a potential risk factor for atherothrombosis, demonstrating that RANKL significantly increases TF expression in macrophages, the major cellular component of atherosclerotic plaques.

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Receptor activator of nuclear factor (NF)–κB ligand (RANKL) increases vascular permeability: impaired permeability and angiogenesis in eNOS-deficient mice

Cited by 98 publications

References 38 publications

A review of therapies for diabetic macular oedema and rationale for combination therapy

A review of therapies for diabetic macular oedema and rationale for combination therapy

Bone metastases in gastric cancer follow a RANKL-independent mechanism

Receptor Activator of Nuclear Factor κB Ligand Is a Novel Inducer of Tissue Factor in Macrophages

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