Vascular Endothelial Growth Factor Up-regulates Expression of Receptor Activator of NF-κB (RANK) in Endothelial Cells

Kim, Jung Min; Kim, Young Myeong; Kim, Eok Cheon; Gho, Yong Song; Kang, Il Jun; Lee, Soo Young; Kong, Young Yun; Kwon, Young Guen

doi:10.1074/jbc.m300539200

Cited by 108 publications

(80 citation statements)

References 49 publications

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“…We observed an increment of transduction signals (RANK and RANK-L) associated both to osteoclast activation, bone remodelling, and inflammatory cell communications [20]. However, since induction of an angiogenic phenotype has been reported to be associated with the up-regulation of RANK/RANK-L signalling [21,22], conceivably this latter event might be related to a functional recovery of injured cells.…”

Section: Discussionmentioning

confidence: 67%

Simulated hypogravity impairs the angiogenic response of endothelium by up-regulating apoptotic signals

Morbidelli

Monici²,

Marziliano

et al. 2005

Biochemical and Biophysical Research Communications

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Health hazards in astronauts are represented by cardiovascular problems and impaired bone healing. These disturbances are characterized by a common event, the loss of function by vascular endothelium, leading to impaired angiogenesis. We investigated whether the exposure of cultured endothelial cells to hypogravity condition could affect their behaviour in terms of functional activity, biochemical responses, morphology, and gene expression. Simulated hypogravity conditions for 72 h produced a reduction of cell number. Genomic analysis of endothelial cells exposed to hypogravity revealed that proapoptotic signals increased, while antiapoptotic and proliferation/survival genes were down-regulated by modelled low gravity. Activation of apoptosis was accompanied by morphological changes with mitochondrial disassembly and organelles/cytoplasmic NAD(P)H redistribution, as evidenced by autofluorescence analysis. In this condition cells were not able to respond to angiogenic stimuli in terms of migration and proliferation. Our study documents functional, morphological, and transcription alterations in vascular endothelium exposed to simulated low gravity conditions, thus providing insights on the occurrence of vascular tissue dysregulation in crewmen during prolonged space flights. Moreover, the alteration of vascular endothelium can intervene as a concause in other systemic effects, like bone remodelling, observed in weightlessness. Ó 2005 Elsevier Inc. All rights reserved.Keywords: Endothelial cell; Hypogravity; Gene expression; Autofluorescence; Apoptosis; Angiogenesis; Migration; Proliferation Angiogenesis, a process which leads to formation of new vessels, has a relevant physiological role during development and in the adult life [1,2]. Endothelial cells are the true player of the angiogenesis process. Several cardiovascular pathologies are caused by endothelial dysfunction (myocardial ischemia, atherosclerosis), thus growth factors and strategies able to restore the integrity of the endothelium and to promote angiogenesis can be viewed as innovative therapeutic approaches [3,4].Indications that mechanical stimulation of cells, and endothelium in particular, is able to change some of their functions at biochemical and molecular level are reported in the literature [5]. In spite of the evidence that cells are sensitive to mechanical stimuli, the molecular mechanisms by which individual cells recognize and respond to external forces are not well understood. Our interest on hypogravity originates from the recognition that several disturbances associated to endothelium-0006-291X/$ -see front matter Ó

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Section: Discussionmentioning

confidence: 67%

Simulated hypogravity impairs the angiogenic response of endothelium by up-regulating apoptotic signals

Morbidelli

Monici²,

Marziliano

et al. 2005

Biochemical and Biophysical Research Communications

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“…RANK mRNA is expressed in many tissues, including skeletal muscle, liver, small intestine and colon, thymus, and adrenal gland (9), yet expression of RANK protein appears to be restricted to osteoclasts and osteoclast precursor cells, T cells, dendritic cells, and endothelial cells (9)(10)(11)32). This study is the first to show that freshly isolated CD14ϩ PBMCs express not only RANK mRNA but also RANK immunoreactivity on their surface, as shown by FACS analysis.…”

Section: Discussionmentioning

confidence: 71%

Expression and function of RANK in human monocyte chemotaxis

Mosheimer

Kaneider

Feistritzer

et al. 2004

Arthritis & Rheumatism

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Objective. RANKL, a member of the tumor necrosis factor superfamily, is a central regulator of osteoclast recruitment and activation. Whether RANKL affects monocyte locomotion in vitro via RANK and a possible signaling pathway were investigated.Methods. Monocytes were obtained from venous blood of healthy donors. Cell migration was studied by micropore filter assays. The signaling mechanisms required for RANKL-dependent migration were tested using signaling enzyme blockers and Western blot analyses. Expression of RANK messenger RNA (mRNA) in monocytes was demonstrated by reverse transcriptasepolymerase chain reaction, and receptor expression on cell surface was investigated by fluorescence-activated cell sorting analyses.Results. RANKL significantly stimulated monocyte chemotaxis via activation of phosphatidylinositol 3-kinase, phosphodiesterase, and Src kinase. The effect on migration was inhibited by osteoprotegerin, which is the decoy receptor for RANKL. Expression of RANK receptor mRNA was shown, and synthesis of RANK in monocytes was suggested by the detection of RANK immunoreactivity on the cell surface.Conclusion. These data suggest that RANK is expressed by monocytes whose activation by RANKL stimulates directed migration involving phosphatidylinositol 3-kinase, phosphodiesterase, and Src kinases.

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“…VEGF increases vascular permeability and leads to airway inflammation (Thurston et al, 2000;Lee et al, 2002;Lee et al, 2004a;Lee et al, 2004b). Recently, it has been reported that VEGF enhances RANK expression in endothelial cells (Min et al, 2003). In this study, we have used OTC, which is a precursor of GSH biosynthesis and thus functioning as an antioxidant, and VEGF receptor inhibitor, SU5614, to examine roles of VEGF in the regulation of the TRANCE receptor RANK expression in OVA-induced asthma murine model.…”

Section: Discussionmentioning

confidence: 99%

“…RANK is detected on mature dendritic cells, chondrocytes, osteoclast precursors, and mature osteoclasts (Wong et al, 1997a;Lacey et al, 1998) and induces activation of extracellular signal-regulated kinase (ERK) and JNK, antiapoptotic serine/threonine kinase Akt/protein kinase B, and NF-B in dendritic cells and osteoclasts (Wong et al, 1997b;Wong et al, 1998;Wong et al, 1999). TRANCE is shown to promote angiogenesis in vivo, and the binding of TRANCE to receptor activator of nuclear factor-B expressed on endothelial cells directly stimulates proliferation, migration, and tube formation of endothelial cells in vitro , and VEGF enhances RANK expression in endothelial cells through Flk-1/KDR-protein kinase C-ERK signaling pathway (Min et al, 2003). Thus, these observations suggest that the TRANCE-RANK system is important for the processes of increases vascular permeability of VEGF.…”

Section: Introductionmentioning

confidence: 99%

An antioxidant modulates expression of receptor activator of NF-κB in asthma

Lee

Park²,

Park³

et al. 2006

Exp Mol Med

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Oxidative stress plays critical roles in airway inflammation that is usually accompanied by increased vascular permeability and plasma exudation. VEGF increases vascular permeability and leads to airway inflammation. In addition, VEGF has been shown to enhance receptor activator of NF-κB (RANK) expression in endothelial cells. An aim of the study was to determine the potential role of antioxidant in the regulation of RANK expression in murine model of asthma. We have used a C57BL/6 mouse model of allergic asthma to evaluate the effect of L-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine, which acts as an antioxidant, and VEGF receptor inhibitor on RANK mRNA expression. The mice develop the following pathophysiological features of asthma in the lungs: increased expression of RANK mRNA, increased number of inflammatory cells of the airways, increased vascular permeability, and increased levels of VEGF. Administration of OTC and VEGF receptor inhibitor markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs. We also showed that the increased RANK mRNA expression at 72 h after ovalbumin inhalation were reduced by the administration of OTC or VEGF receptor inhibitor. The results indicate that OTC and VEGF receptor inhibitor which inhibit up-regulation of VEGF expression modulate RANK expression that may be in association with the regulation of vascular permeability, and suggest that VEGF may regulate the RANK expression. These findings provide a crucial molecular mechanism for the potential use of antioxidants to prevent and/or treat asthma and other airway inflammatory disorders.

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Vascular Endothelial Growth Factor Up-regulates Expression of Receptor Activator of NF-κB (RANK) in Endothelial Cells

Abstract: Vascular endothelial growth factor (VEGF) is known as a key regulator of angiogenesis during endochondral bone formation. Recently, we demonstrated that TNFrelated activation-induced cytokine (TRANCE or RANKL), which is essential for bone remodeling, also had an angiogenic activity.

Cited by 108 publications

References 49 publications

Simulated hypogravity impairs the angiogenic response of endothelium by up-regulating apoptotic signals

Simulated hypogravity impairs the angiogenic response of endothelium by up-regulating apoptotic signals

Expression and function of RANK in human monocyte chemotaxis

An antioxidant modulates expression of receptor activator of NF-κB in asthma

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