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Clinical Sciences |

Association of Inflammatory Factors With Macular Edema in Branch Retinal Vein Occlusion FREE

Hidetaka Noma, MD; Tatsuya Mimura, MD; Shuichiro Eguchi, MD
[+] Author Affiliations

Author Affiliations: Departments of Ophthalmology, Yachiyo Medical Center (Dr Noma) and Medical Center East (Dr Mimura), Tokyo Women's Medical University, Tokyo, and Eguchi Eye Hospital, Hakodate (Dr Eguchi), Japan.


JAMA Ophthalmol. 2013;131(2):160-165. doi:10.1001/2013.jamaophthalmol.228.
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Published online

Objective To evaluate the association between vitreous fluid levels of inflammatory factors and macular edema in patients with branch retinal vein occlusion (BRVO).

Methods In 39 patients with BRVO and macular edema and 21 individuals with idiopathic macular hole (MH) serving as controls, vitreous fluid samples were obtained during vitreoretinal surgery, and the levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR-2), soluble intercellular adhesion molecule 1 (sICAM-1), interleukin 6 (IL-6), monocyte chemotactic protein 1 (MCP-1), pentraxin 3 (PTX3), and pigment epithelium-derived factor (PEDF) were measured by enzyme-linked immunosorbent assay. Macular edema was examined by optical coherence tomography.

Results Vitreous fluid levels of sVEGFR-2, VEGF, sICAM-1, IL-6, MCP-1, and PTX3 were significantly higher in the patients with BRVO than in those with MH; however, the PEDF level was significantly lower in the BRVO group. Vitreous fluid levels of all 7 factors were significantly correlated with the retinal thickness at the central fovea. There were also significant correlations of sVEGFR-2 with sICAM-1, IL-6, MCP-1, and PTX3 but no correlation with VEGF. However, there were significant correlations of VEGF with sICAM-1, IL-6, MCP-1, and PEDF in the BRVO group.

Conclusions Vitreous fluid levels of sVEGFR-2, VEGF, sICAM-1, IL-6, MCP-1, PTX3, and PEDF are strongly correlated with retinal vascular permeability and the severity of macular edema in patients with BRVO. These findings may be useful for understanding macular edema and developing new treatments for BRVO.

Branch retinal vein occlusion (BRVO) often results in macular edema, which is the chief cause of visual impairment in patients with BRVO. Although the pathogenesis of macular edema in these patients is unclear, retinal changes due to BRVO (including hemorrhage) are known to cause local inflammation. After retinal vein occlusion, there is increased rolling and adhesion of leukocytes to the retinal vein walls that lead to stagnation of blood flow,1 so inflammation may play a key role in the pathogenesis of BRVO. The role of inflammation is supported by reports that intravitreal injection of triamcinolone acetonide lessens macular edema in patients with BRVO2 and that the aqueous flare value is significantly higher in patients with retinal vein occlusion than in healthy individuals.3

Various molecules that are secreted into the vitreous fluid may be associated with ocular abnormalities, although the vitreous levels of soluble inflammatory factors might not necessarily reflect their tissue levels, especially the amounts in the retinal microenvironment. However, the concentrations of soluble factors secreted into the vitreous fluid have been reported4 to influence visual prognosis. There is evidence that upregulation of inflammatory factors, including vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR-2), intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), and monocyte chemotactic protein 1 (MCP-1), or downregulation of anti-inflammatory factors, such as pigment epithelium-derived factor (PEDF), and a subsequent increase in leukocyte-endothelial interactions contribute to breakdown of the blood-retinal barrier (BRB).57 The levels of VEGF, IL-6, soluble ICAM-1 (sICAM-1), soluble VEGFR-2 (sVEGFR-2), and PEDF in the vitreous fluid are independently related to vascular permeability in patients with BRVO and macular edema.810 Blocking the actions of inflammatory factors has been shown5 to prevent leukostasis and an increase in retinal vascular permeability in rats, and development of macular edema in patients with BRVO has been reported7,11 to be accompanied by elevation of cytokines that regulate the inflammatory response. Thus, various inflammatory cytokines and other factors influence vascular permeability in the eye and are associated with macular edema in patients with BRVO.

Recently, long pentraxin 3 (PTX3) was reported to be an early indicator of myocardial infarction12 and a predictor of 3-month mortality after acute myocardial events.13 Long pentraxin 3 is an acute-phase protein that is involved in innate immunity and inflammation. Pentraxins are a family of acute response proteins comprising 3 members—C-reactive protein, serum amyloid P, and PTX3—and these proteins are classic acute-phase reactants that closely reflect the level of inflammatory activity.14,15 Long pentraxin 3 is induced by cytokines and is produced mainly by vascular endothelial cells, fibroblasts, and cells in some other extrahepatic tissues,14,1620 unlike the other 2 family members that are synthesized primarily in the liver.21,22 In an animal model, there was a rapid increase in PTX3 expression after reperfusion of the ischemic superior mesenteric artery territory.23 More important, overexpression of PTX3 was accompanied by an increase in death and tissue damage after intestinal ischemia and reperfusion.23 In addition, PTX3 increases vascular permeability.24 These findings suggest that PTX3 may play an important role in the pathogenesis of macular edema associated with BRVO. However, the level of PTX3 expression in patients with BRVO and its relationship to the pathogenesis of macular edema are unclear, just as the relative contribution of each of the molecules evaluated herein to the development of macular edema remains uncertain. Accordingly, we measured the vitreous fluid levels of 6 inflammatory factors (including PTX3) and 1 anti-inflammatory factor in patients with BRVO and macular edema, focusing on molecules that have been linked to the onset or exacerbation of this condition. The association between each of these molecules and the severity of macular edema was then assessed.

PARTICIPANTS

Undiluted vitreous fluid samples were harvested at the start of pars plana vitrectomy (PPV) after written informed consent was obtained from each participant following an explanation of the purpose and potential adverse effects of the procedure. This study was performed in accordance with the Helsinki Declaration of 1975 (1983 revision). The institutional review boards of Tokyo Women's Medical University and Eguchi Eye Hospital approved the protocol for collection and testing of vitreous fluid and blood samples. This was a retrospective case-control study of 60 Japanese patients who underwent PPV in 1 eye (39 with BRVO and 21 with idiopathic macular hole [MH]) to treat macular edema. Seventy-two consecutive patients with BRVO who sought care at the hospitals associated with Tokyo Women's Medical University or Eguchi Eye Hospital between August 11, 2009, and November 15, 2011, were screened, using the criteria listed in the next sentence, and vitreous fluid samples were obtained from the 39 patients enrolled. The indications for PPV were (1) clinically detectable diffuse macular edema or cystoid macular edema persisting for more than 3 months and (2) best-corrected visual acuity worse than 20/40.

The Branch Vein Occlusion Study25 demonstrated the effectiveness of argon laser photocoagulation for BRVO, but it was recommended that this should not be performed within 3 months of occurrence, during which time spontaneous improvement may occur. The absence of posterior vitreous detachment can contribute to persistent macular edema in patients with retinal vascular occlusion.26 Saika et al27 reported on the effectiveness of PPV combined with surgical posterior vitreous detachment for macular edema in patients with BRVO. It has also been reported28,29 that PPV contributes to an increase in oxygen tension in the inner retina. If retinal oxygen tension increases after PPV, macular edema would be lessened for several reasons. First, an increase in oxygen tension would reduce VEGF production and thus decrease vascular permeability. Second, an increase in oxygen tension would alleviate autoregulatory arteriolar vasoconstriction and thus reduce the hydrostatic pressure in the retinal capillaries and venules. This would decrease water flux from the vascular compartment to the tissue compartment and reduce edema according to the Starling law. Finally, PPV reduces the intraocular levels of various other inflammatory factors in addition to VEGF,30 and this may be another mechanism by which it alleviates macular edema in patients with BRVO. In fact, it has been reported31,32 that PPV improves both functional and tomographic outcomes in patients with BRVO and macular edema. Accordingly, we performed PPV in patients with clinically detectable diffuse macular edema or cystoid macular edema more than 3 months after the onset of BRVO.

Thirty-three of the 72 patients were excluded because of previous ocular surgery or intravitreous injection of anti-VEGF agents or triamcinolone acetonide in 23 patients, diabetic retinopathy in 2 patients, previous retinal photocoagulation in 7 patients, and a history of ocular inflammation or vitreoretinal disease in 1 patient. Patients with intravitreous injection of anti-VEGF agents or triamcinolone acetonide were excluded because such treatment could influence vitreous fluid levels of inflammatory factors. Vitreous fluid samples were also obtained from 21 patients with nonischemic ocular diseases as a control group (MH group). None of the patients in the MH group had proliferative vitreoretinopathy. The mean (SD) age of the BRVO group (19 men and 20 women) was 69.2 (9.6) years, and the control group (9 men and 12 women) was aged 68.8 (8.4) years. The mean duration of BRVO was 5.1 (2.4) months (range, 3-11 months). Clinical and laboratory characteristics of the BRVO and MH groups are shown in Table 1.

Table Graphic Jump LocationTable 1. Clinical and Laboratory Characteristics of the BRVO and MH Groups
FUNDUS FINDINGS

Both preoperative and operative fundus findings were recorded for each participant. A masked grader (H.N.) independently assessed ischemic retinal vascular occlusion by examining fluorescein angiograms. The ischemic region of the retina was measured with the public domain Scion Image program (Scion Corp), as reported previously.810 On digital fundus photographs,the disc area was outlined with a cursor and then measured, and the same was done for the nonperfused area. The severity of retinal ischemia was assessed as the nonperfused area divided by the disc area.

Optical coherence tomography was performed in each participant within 1 week before PPV (Zeiss-Humphrey Ophthalmic Systems). The thickness of the central fovea was defined as the distance between the inner limiting membrane and the retinal pigment epithelium (including any serous retinal detachment) and was automatically measured by computer software (Zeiss-Humphrey Ophthalmic System). The thickness of the neurosensory retina was defined as the distance between the inner and outer neurosensory retinal surfaces,26 and the severity of macular edema was graded from the measured retinal thickness.

SAMPLE COLLECTION

Samples of undiluted vitreous fluid (0.5-1.0 mL) were collected at the start of PPV by aspiration into a 1-mL syringe attached to the vitreous cutter before the intravitreal infusion of balanced salt solution was begun. The vitreous samples were immediately transferred into sterile tubes and were rapidly frozen at −80°C. Blood samples were collected simultaneously and were centrifuged at 3000 g for 5 minutes to obtain plasma, after which aliquots were stored at −80°C until assays were performed.

MEASUREMENT OF INFLAMMATORY AND ANTI-INFLAMMATORY FACTORS

The levels of VEGF, sVEGFR-2, sICAM-1, IL-6, MCP-1, and PTX3 were measured in vitreous samples from the same eye and in plasma samples by enzyme-linked immunosorbent assay, using kits for human VEGF, sVEGFR-2, IL-6, MCP-1, and PTX3 (R&D Systems); sICAM-1 (Bender Med Systems); and PTX3 (Perseus Proteomics Inc).8,10,33 Similarly, levels of anti-inflammatory PEDF were measured in vitreous samples with a human PEDF sandwich enzyme-linked immunosorbent assay kit (Chemicon International).9 The VEGF kit was able to detect 2 of the 4 VEGF isoforms (VEGF121 and VEGF165), probably because these 2 shorter isoforms are secreted and the 2 longer isoforms are cell associated. Each assay was performed according to the manufacturer's instructions.

STATISTICAL ANALYSIS

Analyses were performed with commercial software (SAS, version 9.1; SAS Institute Inc). A t test was used to compare normally distributed unpaired continuous variables between the 2 groups, and the Mann-Whitney test was used for variables with a skewed distribution. The χ2 test or Fisher exact test was used to compare discrete variables. Differences between the median plasma and vitreous levels were assessed with the Wilcoxon single rank test. To examine relationships among the variables, Spearman rank order correlation coefficients or Pearson correlation coefficients were calculated. Statistical significance was set at P < .05, with 2-tailed values.

The vitreous fluid concentration of sVEGFR-2 (median [interquartile range]) was significantly higher in the BRVO group (1500 pg/mL [1083-2035]) than in the MH group (1020 pg/mL [721-1343]; P = .002) (Table 2). The vitreous fluid concentration of VEGF was significantly higher in the BRVO group (229 pg/mL [33.9-1353]) compared with the MH group (15.6 pg/mL [15.6-31.2]; P < .001) (Table 2). Likewise, vitreous sICAM-1 levels were significantly higher in the BRVO group (8.20 ng/mL [5.33-15.6]) than in the MH group (4.50 ng/mL [3.60-5.65]; P < .001) (Table 2). Furthermore, the vitreous level of IL-6 was significantly higher in the BRVO group (10.7 pg/mL [5.53-29.0]) than in the MH group (1.00 pg/mL [0.50-1.18]; P < .001), as was the vitreous level of MCP-1 (1190 pg/mL [747-1993] vs 458 pg/mL [375-636]; P < .001) and the vitreous level of PTX3 (0.86 ng/mL [0.50-1.62] vs 0.50 ng/mL [0.50-0.81]; P = .01) (Table 2). In contrast, the vitreous fluid level of PEDF was significantly lower in the BRVO group (25.6 ng/mL [8.14-40.7]) than in the MH group (59.9 ng/mL [25.0-101]; P = .005) (Table 2).

Table Graphic Jump LocationTable 2. Vitreous Fluid Levels of Factors in the Groups

Vitreous fluid levels of VEGF, sICAM-1, IL-6, MCP-1, and PTX3 were significantly correlated with the nonperfused area of the retina in the BRVO group (r = 0.77, P < .001; r = 0.36, P = .02; r = 0.46, P = .004; r = 0.52, P = .001; and r = 0.37, P = .02, respectively) (Table 3). Conversely, the vitreous fluid level of PEDF showed a significant negative correlation with the nonperfused area in the BRVO group (r = −0.39, P = .02) (Table 3). However, the vitreous fluid level of sVEGFR-2 was not significantly correlated with the nonperfused area in this group (r = 0.19, P = .25) (Table 3).

Table Graphic Jump LocationTable 3. Correlation of Vitreous Factors With the Nonperfused Area and Retinal Thickness

Vitreous fluid levels of sVEGFR-2, VEGF, sICAM-1, IL-6, MCP-1, PTX3, and PEDF were significantly correlated with the retinal thickness at the central fovea according to simple linear regression analysis (r = 0.36, P = .02; r = 0.47, P = .003; r = 0.56, P < .001; r = 0.41, P = .01; r = 0.63, P < .001; r = 0.39, P = .02; and r = −0.36, P = .02, respectively) (Table 3).

In the BRVO group, there were significant correlations between the vitreous fluid level of sVEGFR-2 and the levels of sICAM-1, IL-6, MCP-1, and PTX3 (r = 0.76, P < .001; r = 0.63, P < .001; r = 0.69, P < .001; and r = 0.66, P < .001; respectively) (Table 4). There were also significant correlations between the vitreous fluid level of VEGF and the levels of sICAM-1, IL-6, MCP-1, and PEDF in the BRVO group (r = 0.34, P = .03; r = 0.41, P = .01; r = 0.46, P = .004; and r = −0.33, P = .04, respectively) (Table 4). Furthermore, there was a significant correlation between the vitreous fluid level of sICAM-1 and the levels of IL-6, MCP-1, and PTX3 (r = 0.63, P < .001; r = 0.66, P < .001; and r = 0.64, P < .001, respectively) (Table 4). Moreover, there was a significant correlation between the vitreous fluid level of IL-6 and the levels of MCP-1 and PTX3 (r = 0.70, P < .001; and r = 0.65, P < .001, respectively) (Table 4), as well as a significant correlation between MCP-1 and PTX3 or PEDF (r = 0.53, P < .001; and r = −0.39, P = .02, respectively) (Table 4). In contrast, there was no significant correlation between the vitreous levels of sVEGFR-2 and VEGF (r = 0.14, P = .38) or between the vitreous levels of VEGF and PTX3 in the BRVO group (r = 0.23, P = .19) (Table 4). There were also no significant correlations between the vitreous level of PEDF and the levels of sVEGFR-2, sICAM-1, IL-6, and PTX3 in the BRVO group (r = −0.12, P = .44; r = 0.03, P = .87; r = −0.10, P = .52; and r = 0.04, P = .82, respectively) (Table 4).

Table Graphic Jump LocationTable 4. Correlation Matrix for Vitreous Factors

In the BRVO group, the vitreous fluid levels of VEGF, IL-6, and MCP-1 were significantly higher (all P < .001) than the plasma levels of these molecules (18.1 pg/mL [15.6-44.1], 0.59 pg/mL [0.35-0.98], and 142 pg/mL [117-167], respectively), whereas the vitreous levels of sVEGFR-2, sICAM-1, and PTX3 were significantly lower (all P < .001) than their plasma levels (6750 pg/mL [5895-8245], 423 ng/mL [332-508], and 3.66 ng/mL [2.66-5.11], respectively).

There were 3 main findings in this study. First, vitreous fluid levels of sVEGFR-2, VEGF, sICAM-1, IL-6, MCP-1, and PTX3 were significantly higher in patients with BRVO and macular edema than in controls with MH. Second, vitreous fluid levels of sVEGFR-2, VEGF, sICAM-1, IL-6, MCP-1, PTX3, and PEDF were also correlated with the retinal thickness at the central fovea. Finally, there were significant correlations among the vitreous fluid levels of sICAM-1, IL-6, MCP-1, PTX3, and sVEGFR-2 in the BRVO group, as well as among the vitreous levels of sICAM-1, IL-6, MCP-1, PEDF, and VEGF.

These findings suggest that not only VEGF but also VEGFR-2, ICAM-1, IL-6, MCP-1, and PTX3 may play important roles in the occurrence of macular edema associated with BRVO. Vascular endothelial growth factor has a potent influence on vascular permeability, and its production is upregulated by retinal hypoxia in patients with BRVO and macular edema.8 Breakdown of the BRB and retinal vascular hyperpermeability are important pathophysiologic features of macular edema associated with BRVO, and there is evidence that inflammation is a key mediator of both endothelial cell damage and BRB breakdown.57 Upregulation of inflammatory factors, including VEGF, VEGFR-2, ICAM-1, IL-6, and MCP-1, as well as increased rolling and adhesion of leukocytes, is observed before and during the increase in retinal permeability.57 Leukocyte recruitment is modulated by PTX3 in inflammation,34 so its upregulation could also lead to an increase in vascular permeability.24 This possibility is supported by the report24 that the response of vascular permeability is less marked in PTX3-deficient mice. Thus, interactions among the network of inflammatory factors evaluated here may enhance vascular permeability. Activation of ICAM-1 and the subsequent increase in leukocyte-endothelial adhesion may be essential for VEGF to induce vascular hyperpermeability5 because blocking ICAM-1 activity almost completely prevents VEGF-induced leukostasis and BRB breakdown.35 However, blocking VEGF activity in the diabetic retina markedly reduces the upregulation of ICAM-1 as well as the increase in leukocyte adhesion and BRB breakdown.36 These findings suggest that VEGF is the key factor mediating the response to hypoxia in the retina.

Interestingly, we found a significant correlation between the vitreous fluid level of sVEGFR-2 and the levels of various inflammatory factors (sICAM-1, IL-6, MCP-1, and PTX3) in patients with BRVO and macular edema, but there was no significant correlation between the vitreous fluid levels of sVEGFR-2 and VEGF. Binding of VEGF to VEGFR-2 triggers a signaling cascade that results in tyrosine phosphorylation of phospholipase Cγ,3739 which in turn increases the intracellular levels of inositol 1,4,5-triphosphate and diacylglycerol. Inositol 1,4,5-triphosphate increases the intracellular calcium level by promoting efflux of calcium from the endoplasmic reticulum. This increase in intracellular calcium stimulates sphingosine kinase to produce sphingosine 1-phosphate,40 which then activates protein kinase C (PKC). Activated phospholipase Cγ also activates PKC by increasing the level of diacylglycerol, and activated PKC is a strong activator of nuclear factor κ B (NF-κB).41 There is ample evidence that NF-κB promotes the transcription of inflammatory factors (including ICAM-1, IL-6, and MCP-1).4247 Nuclear factor–κB is found in almost all cell types and is involved in cellular responses to stimuli such as stress, proinflammatory gene expression (including cytokines, adhesion molecules, and chemokines), free radicals, UV irradiation, and bacterial or viral antigens in addition to its central role in the immune response.4850 It has also been reported5154 that VEGF, via the VEGFR-2–PKC axis, induces the production of proinflammatory cytokines (including IL-6 and MCP-1) in endothelial cells. Thus, VEGF promotes the expression of inflammatory factor messenger RNAs (including ICAM-1, IL-6, and MCP-1), mainly through the activation of PKC and NF-κB, indicating that VEGF induces the expression of inflammatory proteins by vascular endothelial cells through binding to VEGFR-2. This is supported by reports53,55,56 that a specific VEGFR-2 antagonist blocks VEGF-induced expression of inflammatory factors (including ICAM-1, IL-6, and MCP-1) and also blocks activation of NF-κB by VEGF. Expression of the PTX3 gene also requires the activation of NF-κB.57 In addition, Souza et al24 reported that NF-κB activation was significantly suppressed in PTX3-deficient mice. Taken together with our results, these reports suggest that the vitreous level of sVEGFR-2 influences various inflammatory factors (including ICAM-1, IL-6, MCP-1, and PTX3) in patients with BRVO and macular edema. On the other hand, the vitreous level of sVEGFR-2 may be regulated independently of VEGF, although the VEGF–VEGFR-2 signaling pathway is considered essential for controlling vascular permeability.58,59 The VEGF is upregulated by hypoxia through hypoxia-inducible factor 1α,60 which is another transcription factor that regulates genes responding to hypoxia.61 Vascular endothelial growth factor may act via an independent pathway to promote the retinal changes that occur in BRVO; therefore, additional studies are required to identify the mechanism. Differences in the activation of various transcription factors may determine the severity of ocular ischemic and inflammatory changes.

Considering our results, as well as the balance between VEGF and inflammatory cytokines, we should select treatment with anti-VEGF agents (to reduce the level of free VEGF) or triamcinolone acetonide (with a broad spectrum of action, as appropriate). Because the aqueous level of VEGF is significantly correlated with the vitreous level of VEGF,62 measuring the concentrations of various molecules in aqueous humor by enzyme-linked immunosorbent assay or multiplex bead analysis could help with the selection of treatment between anti-VEGF agents, triamcinolone acetonide, or combined therapy. In addition, upregulation of inflammatory factors may be dependent on VEGFR-2 because there were significant correlations between the vitreous fluid level of sVEGFR-2 and the vitreous levels of 4 inflammatory factors (sICAM-1, IL-6, MCP-1, and PTX3) in our patients with BRVO and macular edema. Accordingly, multiple inflammatory factors could be inhibited by an antibody targeting VEGFR-2, so it may be worth also considering anti–VEGFR-2 therapy to treat macular edema in this population. However, a prospective clinical trial would be required to investigate the efficacy of such therapy.

This study also had some other limitations. For example, it is unclear from our data whether elevated vitreous levels of cytokines and chemokines were related to increased retinal vascular permeability or local production in the retina, but the mechanism involved may be revealed by animal studies.

In the present study, the vitreous fluid levels of sVEGFR-2, VEGF, sICAM-1, IL-6, MCP-1, PTX3, and PEDF were strongly correlated with retinal vascular permeability and the severity of macular edema. The sVEGFR-2 level was significantly correlated with the levels of sICAM-1, IL-6, MCP-1, and PTX3 but not with the level of VEGF. These findings suggest the importance of investigating relationships among VEGF and the cytokine network and may contribute to understanding the mechanism of macular edema in patients with BRVO and developing new treatments.

Correspondence: Hidetaka Noma, MD, Department of Ophthalmology, Yachiyo Medical Center, Tokyo Women's Medical University, 477-96, Owada-shinden, Yachiyo, Chiba 276-8524, Japan (noma-hide@umin.ac.jp).

Submitted for Publication: May 9, 2012; final revision received July 20, 2012; accepted July 24, 2012.

Author Contributions: Dr Noma had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of Interest Disclosures: None reported.

Additional Contributions: Katsunori Shimada, PhD (Department of Biostatistics, Statz Corporation, Tokyo), provided assistance with the statistical analysis.

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Klouche M, Peri G, Knabbe C,  et al.  Modified atherogenic lipoproteins induce expression of pentraxin-3 by human vascular smooth muscle cells.  Atherosclerosis. 2004;175(2):221-228
PubMed   |  Link to Article
Toniatti C, Demartis A, Monaci P, Nicosia A, Ciliberto G. Synergistic trans -activation of the human C-reactive protein promoter by transcription factor HNF-1 binding at two distinct sites.  EMBO J. 1990;9(13):4467-4475
PubMed
Pepys MB, Hirschfield GM. C-reactive protein: a critical update.  J Clin Invest. 2003;111(12):1805-1812
PubMed
Souza DG, Soares AC, Pinho V,  et al.  Increased mortality and inflammation in tumor necrosis factor–stimulated gene-14 transgenic mice after ischemia and reperfusion injury.  Am J Pathol. 2002;160(5):1755-1765
PubMed   |  Link to Article
Souza DG, Amaral FA, Fagundes CT,  et al.  The long pentraxin PTX3 is crucial for tissue inflammation after intestinal ischemia and reperfusion in mice.  Am J Pathol. 2009;174(4):1309-1318
PubMed   |  Link to Article
Branch Vein Occlusion Study Group.  Argon laser photocoagulation for macular edema in branch vein occlusion.  Am J Ophthalmol. 1984;98(3):271-282
PubMed
Otani T, Kishi S. Tomographic assessment of vitreous surgery for diabetic macular edema.  Am J Ophthalmol. 2000;129(4):487-494
PubMed   |  Link to Article
Saika S, Tanaka T, Miyamoto T, Ohnishi Y. Surgical posterior vitreous detachment combined with gas/air tamponade for treating macular edema associated with branch retinal vein occlusion: retinal tomography and visual outcome.  Graefes Arch Clin Exp Ophthalmol. 2001;239(10):729-732
PubMed   |  Link to Article
Stefánsson E, Novack RL, Hatchell DL. Vitrectomy prevents retinal hypoxia in branch retinal vein occlusion.  Invest Ophthalmol Vis Sci. 1990;31(2):284-289
PubMed
Stefánsson E. Ocular oxygenation and the treatment of diabetic retinopathy.  Surv Ophthalmol. 2006;51(4):364-380
PubMed   |  Link to Article
Okunuki Y, Usui Y, Katai N,  et al.  Relation of intraocular concentrations of inflammatory factors and improvement of macular edema after vitrectomy in branch retinal vein occlusion.  Am J Ophthalmol. 2011;151(4):610-616.e1Link to Article
PubMed   |  Link to Article
Yamamoto S, Saito W, Yagi F, Takeuchi S, Sato E, Mizunoya S. Vitrectomy with or without arteriovenous adventitial sheathotomy for macular edema associated with branch retinal vein occlusion.  Am J Ophthalmol. 2004;138(6):907-914
PubMed   |  Link to Article
Kumagai K, Furukawa M, Ogino N, Uemura A, Larson E. Long-term outcomes of vitrectomy with or without arteriovenous sheathotomy in branch retinal vein occlusion.  Retina. 2007;27(1):49-54
PubMed   |  Link to Article
Funatsu H, Noma H, Mimura T, Eguchi S, Hori S. Association of vitreous inflammatory factors with diabetic macular edema.  Ophthalmology. 2009;116(1):73-79
PubMed   |  Link to Article
Deban L, Russo RC, Sironi M,  et al.  Regulation of leukocyte recruitment by the long pentraxin PTX3.  Nat Immunol. 2010;11(4):328-334
PubMed   |  Link to Article
Miyamoto K, Khosrof S, Bursell SE,  et al.  Vascular endothelial growth factor (VEGF)–induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1).  Am J Pathol. 2000;156(5):1733-1739
PubMed   |  Link to Article
Ishida S, Usui T, Yamashiro K,  et al.  VEGF164 is proinflammatory in the diabetic retina.  Invest Ophthalmol Vis Sci. 2003;44(5):2155-2162
PubMed   |  Link to Article
Xia P, Aiello LP, Ishii H,  et al.  Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth.  J Clin Invest. 1996;98(9):2018-2026
PubMed   |  Link to Article
He H, Venema VJ, Gu X, Venema RC, Marrero MB, Caldwell RB. Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src.  J Biol Chem. 1999;274(35):25130-25135
PubMed   |  Link to Article
Wu LW, Mayo LD, Dunbar JD,  et al.  Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation.  J Biol Chem. 2000;275(7):5096-5103
PubMed   |  Link to Article
Olivera A, Edsall L, Poulton S, Kazlauskas A, Spiegel S. Platelet-derived growth factor–induced activation of sphingosine kinase requires phosphorylation of the PDGF receptor tyrosine residue responsible for binding of PLCγ.  FASEB J. 1999;13(12):1593-1600
PubMed
Ghosh S, Baltimore D. Activation in vitro of NF-κB by phosphorylation of its inhibitor IκB.  Nature. 1990;344(6267):678-682
PubMed   |  Link to Article
Matsusaka T, Fujikawa K, Nishio Y,  et al.  Transcription factors NF-IL6 and NF-κB synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8.  Proc Natl Acad Sci U S A. 1993;90(21):10193-10197
PubMed   |  Link to Article
Ledebur HC, Parks TP. Transcriptional regulation of the intercellular adhesion molecule-1 gene by inflammatory cytokines in human endothelial cells: essential roles of a variant NF-κB site and p65 homodimers.  J Biol Chem. 1995;270(2):933-943
PubMed   |  Link to Article
Wrighton CJ, Hofer-Warbinek R, Moll T, Eytner R, Bach FH, de Martin R. Inhibition of endothelial cell activation by adenovirus-mediated expression of IκBα, an inhibitor of the transcription factor NF-κB.  J Exp Med. 1996;183(3):1013-1022
PubMed   |  Link to Article
Baldwin AS Jr. The NF-κB and IκB proteins: new discoveries and insights.  Annu Rev Immunol. 1996;14:649-683
PubMed   |  Link to Article
Marumo T, Schini-Kerth VB, Fisslthaler B, Busse R. Platelet-derived growth factor–stimulated superoxide anion production modulates activation of transcription factor NF-κB and expression of monocyte chemoattractant protein 1 in human aortic smooth muscle cells.  Circulation. 1997;96(7):2361-2367
PubMed   |  Link to Article
Boyle EM Jr, Kovacich JC, Canty TG Jr,  et al.  Inhibition of nuclear factor-κB nuclear localization reduces human E-selectin expression and the systemic inflammatory response.  Circulation. 1998;98(19):(suppl)  II282-II288
PubMed
Barnes PJ, Karin M. Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases.  N Engl J Med. 1997;336(15):1066-1071
PubMed   |  Link to Article
Ghosh S, May MJ, Kopp EB. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses.  Annu Rev Immunol. 1998;16:225-260
PubMed   |  Link to Article
Perkins ND. Integrating cell-signalling pathways with NF-κB and IKK function.  Nat Rev Mol Cell Biol. 2007;8(1):49-62
PubMed   |  Link to Article
Carnevale KA, Cathcart MK. Protein kinase C β is required for human monocyte chemotaxis to MCP-1.  J Biol Chem. 2003;278(28):25317-25322
PubMed   |  Link to Article
Hong KH, Ryu J, Han KH. Monocyte chemoattractant protein-1–induced angiogenesis is mediated by vascular endothelial growth factor-A.  Blood. 2005;105(4):1405-1407
PubMed   |  Link to Article
Koga J, Matoba T, Egashira K,  et al.  Soluble Flt-1 gene transfer ameliorates neointima formation after wire injury in flt-1 tyrosine kinase–deficient mice.  Arterioscler Thromb Vasc Biol. 2009;29(4):458-464
PubMed   |  Link to Article
Hao Q, Wang L, Tang H. Vascular endothelial growth factor induces protein kinase D–dependent production of proinflammatory cytokines in endothelial cells.  Am J Physiol Cell Physiol. 2009;296(4):C821-C827
PubMed   |  Link to Article
Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY. Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-κB activation in endothelial cells.  J Biol Chem. 2001;276(10):7614-7620
PubMed   |  Link to Article
Yao JS, Zhai W, Young WL, Yang GY. Interleukin-6 triggers human cerebral endothelial cells proliferation and migration: the role for KDR and MMP-9.  Biochem Biophys Res Commun. 2006;342(4):1396-1404
PubMed   |  Link to Article
Basile A, Sica A, d’Aniello E,  et al.  Characterization of the promoter for the human long pentraxin PTX3: role of NF-κB in tumor necrosis factor–α and interleukin-1β regulation.  J Biol Chem. 1997;272(13):8172-8178
PubMed   |  Link to Article
Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor.  Endocr Rev. 1997;18(1):4-25
PubMed   |  Link to Article
Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors.  Biochem Soc Trans. 2003;31(pt 1):20-24
PubMed
Forsythe JA, Jiang BH, Iyer NV,  et al.  Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.  Mol Cell Biol. 1996;16(9):4604-4613
PubMed
Pagès G, Pouysségur J. Transcriptional regulation of the vascular endothelial growth factor gene—a concert of activating factors.  Cardiovasc Res. 2005;65(3):564-573
PubMed   |  Link to Article
Noma H, Funatsu H, Yamasaki M,  et al.  Aqueous humour levels of cytokines are correlated to vitreous levels and severity of macular oedema in branch retinal vein occlusion.  Eye (Lond). 2008;22(1):42-48
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Clinical and Laboratory Characteristics of the BRVO and MH Groups
Table Graphic Jump LocationTable 2. Vitreous Fluid Levels of Factors in the Groups
Table Graphic Jump LocationTable 3. Correlation of Vitreous Factors With the Nonperfused Area and Retinal Thickness
Table Graphic Jump LocationTable 4. Correlation Matrix for Vitreous Factors

References

Tsujikawa A, Ogura Y, Hiroshiba N, Miyamoto K, Kiryu J, Honda Y. In vivo evaluation of leukocyte dynamics in retinal ischemia reperfusion injury.  Invest Ophthalmol Vis Sci. 1998;39(5):793-800
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Scott IU, Ip MS, VanVeldhuisen PC,  et al; SCORE Study Research Group.  A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6.  Arch Ophthalmol. 2009;127(9):1115-1128
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Miyake K, Miyake T, Kayazawa F. Blood-aqueous barrier in eyes with retinal vein occlusion.  Ophthalmology. 1992;99(6):906-910
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Noma H, Funatsu H, Mimura T, Eguchi S, Shimada K. Visual prognosis and vitreous molecules after vitrectomy for macular edema with branch retinal vein occlusion.  Clin Ophthalmol. 2011;5:223-229
PubMed   |  Link to Article
Lu M, Perez VL, Ma N,  et al.  VEGF increases retinal vascular ICAM-1 expression in vivo.  Invest Ophthalmol Vis Sci. 1999;40(8):1808-1812
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Zhang SX, Wang JJ, Gao G, Shao C, Mott R, Ma JX. Pigment epithelium–derived factor (PEDF) is an endogenous antiinflammatory factor.  FASEB J. 2006;20(2):323-325
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Yoshimura T, Sonoda KH, Sugahara M,  et al.  Comprehensive analysis of inflammatory immune mediators in vitreoretinal diseases.  PLoS One. 2009;4(12):e8158Link to Article
PubMed   |  Link to Article
Noma H, Minamoto A, Funatsu H,  et al.  Intravitreal levels of vascular endothelial growth factor and interleukin-6 are correlated with macular edema in branch retinal vein occlusion.  Graefes Arch Clin Exp Ophthalmol. 2006;244(3):309-315
PubMed   |  Link to Article
Noma H, Funatsu H, Mimura T, Harino S, Eguchi S, Hori S. Pigment epithelium-derived factor and vascular endothelial growth factor in branch retinal vein occlusion with macular edema.  Graefes Arch Clin Exp Ophthalmol. 2010;248(11):1559-1565
PubMed   |  Link to Article
Noma H, Funatsu H, Mimura T, Eguchi S, Hori S. Soluble vascular endothelial growth factor receptor-2 and inflammatory factors in macular edema with branch retinal vein occlusion.  Am J Ophthalmol. 2011;152(4):669-677.e1Link to Article
PubMed   |  Link to Article
Kaneda S, Miyazaki D, Sasaki S,  et al.  Multivariate analyses of inflammatory cytokines in eyes with branch retinal vein occlusion: relationships to bevacizumab treatment.  Invest Ophthalmol Vis Sci. 2011;52(6):2982-2988
PubMed   |  Link to Article
Peri G, Introna M, Corradi D,  et al.  PTX3, a prototypical long pentraxin, is an early indicator of acute myocardial infarction in humans.  Circulation. 2000;102(6):636-641
PubMed   |  Link to Article
Latini R, Maggioni AP, Peri G,  et al; Lipid Assessment Trial Italian Network (LATIN) Investigators.  Prognostic significance of the long pentraxin PTX3 in acute myocardial infarction.  Circulation. 2004;110(16):2349-2354
PubMed   |  Link to Article
Breviario F, d’Aniello EM, Golay J,  et al.  Interleukin-1–inducible genes in endothelial cells: cloning of a new gene related to C-reactive protein and serum amyloid P component.  J Biol Chem. 1992;267(31):22190-22197
PubMed
Garlanda C, Bottazzi B, Bastone A, Mantovani A. Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility.  Annu Rev Immunol. 2005;23:337-366
PubMed   |  Link to Article
Alles VV, Bottazzi B, Peri G, Golay J, Introna M, Mantovani A. Inducible expression of PTX3, a new member of the pentraxin family, in human mononuclear phagocytes.  Blood. 1994;84(10):3483-3493
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Introna M, Alles VV, Castellano M,  et al.  Cloning of mouse ptx3, a new member of the pentraxin gene family expressed at extrahepatic sites.  Blood. 1996;87(5):1862-1872
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Goodman AR, Levy DE, Reis LF, Vilcek J. Differential regulation of TSG-14 expression in murine fibroblasts and peritoneal macrophages.  J Leukoc Biol. 2000;67(3):387-395
PubMed
Doni A, Peri G, Chieppa M,  et al.  Production of the soluble pattern recognition receptor PTX3 by myeloid, but not plasmacytoid, dendritic cells.  Eur J Immunol. 2003;33(10):2886-2893
PubMed   |  Link to Article
Klouche M, Peri G, Knabbe C,  et al.  Modified atherogenic lipoproteins induce expression of pentraxin-3 by human vascular smooth muscle cells.  Atherosclerosis. 2004;175(2):221-228
PubMed   |  Link to Article
Toniatti C, Demartis A, Monaci P, Nicosia A, Ciliberto G. Synergistic trans -activation of the human C-reactive protein promoter by transcription factor HNF-1 binding at two distinct sites.  EMBO J. 1990;9(13):4467-4475
PubMed
Pepys MB, Hirschfield GM. C-reactive protein: a critical update.  J Clin Invest. 2003;111(12):1805-1812
PubMed
Souza DG, Soares AC, Pinho V,  et al.  Increased mortality and inflammation in tumor necrosis factor–stimulated gene-14 transgenic mice after ischemia and reperfusion injury.  Am J Pathol. 2002;160(5):1755-1765
PubMed   |  Link to Article
Souza DG, Amaral FA, Fagundes CT,  et al.  The long pentraxin PTX3 is crucial for tissue inflammation after intestinal ischemia and reperfusion in mice.  Am J Pathol. 2009;174(4):1309-1318
PubMed   |  Link to Article
Branch Vein Occlusion Study Group.  Argon laser photocoagulation for macular edema in branch vein occlusion.  Am J Ophthalmol. 1984;98(3):271-282
PubMed
Otani T, Kishi S. Tomographic assessment of vitreous surgery for diabetic macular edema.  Am J Ophthalmol. 2000;129(4):487-494
PubMed   |  Link to Article
Saika S, Tanaka T, Miyamoto T, Ohnishi Y. Surgical posterior vitreous detachment combined with gas/air tamponade for treating macular edema associated with branch retinal vein occlusion: retinal tomography and visual outcome.  Graefes Arch Clin Exp Ophthalmol. 2001;239(10):729-732
PubMed   |  Link to Article
Stefánsson E, Novack RL, Hatchell DL. Vitrectomy prevents retinal hypoxia in branch retinal vein occlusion.  Invest Ophthalmol Vis Sci. 1990;31(2):284-289
PubMed
Stefánsson E. Ocular oxygenation and the treatment of diabetic retinopathy.  Surv Ophthalmol. 2006;51(4):364-380
PubMed   |  Link to Article
Okunuki Y, Usui Y, Katai N,  et al.  Relation of intraocular concentrations of inflammatory factors and improvement of macular edema after vitrectomy in branch retinal vein occlusion.  Am J Ophthalmol. 2011;151(4):610-616.e1Link to Article
PubMed   |  Link to Article
Yamamoto S, Saito W, Yagi F, Takeuchi S, Sato E, Mizunoya S. Vitrectomy with or without arteriovenous adventitial sheathotomy for macular edema associated with branch retinal vein occlusion.  Am J Ophthalmol. 2004;138(6):907-914
PubMed   |  Link to Article
Kumagai K, Furukawa M, Ogino N, Uemura A, Larson E. Long-term outcomes of vitrectomy with or without arteriovenous sheathotomy in branch retinal vein occlusion.  Retina. 2007;27(1):49-54
PubMed   |  Link to Article
Funatsu H, Noma H, Mimura T, Eguchi S, Hori S. Association of vitreous inflammatory factors with diabetic macular edema.  Ophthalmology. 2009;116(1):73-79
PubMed   |  Link to Article
Deban L, Russo RC, Sironi M,  et al.  Regulation of leukocyte recruitment by the long pentraxin PTX3.  Nat Immunol. 2010;11(4):328-334
PubMed   |  Link to Article
Miyamoto K, Khosrof S, Bursell SE,  et al.  Vascular endothelial growth factor (VEGF)–induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1).  Am J Pathol. 2000;156(5):1733-1739
PubMed   |  Link to Article
Ishida S, Usui T, Yamashiro K,  et al.  VEGF164 is proinflammatory in the diabetic retina.  Invest Ophthalmol Vis Sci. 2003;44(5):2155-2162
PubMed   |  Link to Article
Xia P, Aiello LP, Ishii H,  et al.  Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth.  J Clin Invest. 1996;98(9):2018-2026
PubMed   |  Link to Article
He H, Venema VJ, Gu X, Venema RC, Marrero MB, Caldwell RB. Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src.  J Biol Chem. 1999;274(35):25130-25135
PubMed   |  Link to Article
Wu LW, Mayo LD, Dunbar JD,  et al.  Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation.  J Biol Chem. 2000;275(7):5096-5103
PubMed   |  Link to Article
Olivera A, Edsall L, Poulton S, Kazlauskas A, Spiegel S. Platelet-derived growth factor–induced activation of sphingosine kinase requires phosphorylation of the PDGF receptor tyrosine residue responsible for binding of PLCγ.  FASEB J. 1999;13(12):1593-1600
PubMed
Ghosh S, Baltimore D. Activation in vitro of NF-κB by phosphorylation of its inhibitor IκB.  Nature. 1990;344(6267):678-682
PubMed   |  Link to Article
Matsusaka T, Fujikawa K, Nishio Y,  et al.  Transcription factors NF-IL6 and NF-κB synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8.  Proc Natl Acad Sci U S A. 1993;90(21):10193-10197
PubMed   |  Link to Article
Ledebur HC, Parks TP. Transcriptional regulation of the intercellular adhesion molecule-1 gene by inflammatory cytokines in human endothelial cells: essential roles of a variant NF-κB site and p65 homodimers.  J Biol Chem. 1995;270(2):933-943
PubMed   |  Link to Article
Wrighton CJ, Hofer-Warbinek R, Moll T, Eytner R, Bach FH, de Martin R. Inhibition of endothelial cell activation by adenovirus-mediated expression of IκBα, an inhibitor of the transcription factor NF-κB.  J Exp Med. 1996;183(3):1013-1022
PubMed   |  Link to Article
Baldwin AS Jr. The NF-κB and IκB proteins: new discoveries and insights.  Annu Rev Immunol. 1996;14:649-683
PubMed   |  Link to Article
Marumo T, Schini-Kerth VB, Fisslthaler B, Busse R. Platelet-derived growth factor–stimulated superoxide anion production modulates activation of transcription factor NF-κB and expression of monocyte chemoattractant protein 1 in human aortic smooth muscle cells.  Circulation. 1997;96(7):2361-2367
PubMed   |  Link to Article
Boyle EM Jr, Kovacich JC, Canty TG Jr,  et al.  Inhibition of nuclear factor-κB nuclear localization reduces human E-selectin expression and the systemic inflammatory response.  Circulation. 1998;98(19):(suppl)  II282-II288
PubMed
Barnes PJ, Karin M. Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases.  N Engl J Med. 1997;336(15):1066-1071
PubMed   |  Link to Article
Ghosh S, May MJ, Kopp EB. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses.  Annu Rev Immunol. 1998;16:225-260
PubMed   |  Link to Article
Perkins ND. Integrating cell-signalling pathways with NF-κB and IKK function.  Nat Rev Mol Cell Biol. 2007;8(1):49-62
PubMed   |  Link to Article
Carnevale KA, Cathcart MK. Protein kinase C β is required for human monocyte chemotaxis to MCP-1.  J Biol Chem. 2003;278(28):25317-25322
PubMed   |  Link to Article
Hong KH, Ryu J, Han KH. Monocyte chemoattractant protein-1–induced angiogenesis is mediated by vascular endothelial growth factor-A.  Blood. 2005;105(4):1405-1407
PubMed   |  Link to Article
Koga J, Matoba T, Egashira K,  et al.  Soluble Flt-1 gene transfer ameliorates neointima formation after wire injury in flt-1 tyrosine kinase–deficient mice.  Arterioscler Thromb Vasc Biol. 2009;29(4):458-464
PubMed   |  Link to Article
Hao Q, Wang L, Tang H. Vascular endothelial growth factor induces protein kinase D–dependent production of proinflammatory cytokines in endothelial cells.  Am J Physiol Cell Physiol. 2009;296(4):C821-C827
PubMed   |  Link to Article
Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY. Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-κB activation in endothelial cells.  J Biol Chem. 2001;276(10):7614-7620
PubMed   |  Link to Article
Yao JS, Zhai W, Young WL, Yang GY. Interleukin-6 triggers human cerebral endothelial cells proliferation and migration: the role for KDR and MMP-9.  Biochem Biophys Res Commun. 2006;342(4):1396-1404
PubMed   |  Link to Article
Basile A, Sica A, d’Aniello E,  et al.  Characterization of the promoter for the human long pentraxin PTX3: role of NF-κB in tumor necrosis factor–α and interleukin-1β regulation.  J Biol Chem. 1997;272(13):8172-8178
PubMed   |  Link to Article
Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor.  Endocr Rev. 1997;18(1):4-25
PubMed   |  Link to Article
Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors.  Biochem Soc Trans. 2003;31(pt 1):20-24
PubMed
Forsythe JA, Jiang BH, Iyer NV,  et al.  Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.  Mol Cell Biol. 1996;16(9):4604-4613
PubMed
Pagès G, Pouysségur J. Transcriptional regulation of the vascular endothelial growth factor gene—a concert of activating factors.  Cardiovasc Res. 2005;65(3):564-573
PubMed   |  Link to Article
Noma H, Funatsu H, Yamasaki M,  et al.  Aqueous humour levels of cytokines are correlated to vitreous levels and severity of macular oedema in branch retinal vein occlusion.  Eye (Lond). 2008;22(1):42-48
PubMed   |  Link to Article

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