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Plasma VEGF and Soluble VEGF Receptor FLT-1 in Proliferative Retinopathy: Relationship to Endothelial Dysfunction and Laser Treatment

¹ From the Haemostasis, Thrombosis, and Vascular Biology Unit, University Department of Medicine, and ² Birmingham and Midland Eye Centre, City Hospital, Birmingham, United Kingdom.

	Abstract

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PURPOSE. To study plasma levels of vascular endothelial growth factor (VEGF, an index of angiogenesis), its soluble receptor (sFlt-1) and von Willebrand factor (vWf, an index of endothelial damage or dysfunction) in patients with proliferative retinopathy and corresponding changes in plasma levels after pan-retinal photocoagulation (PRP).

METHODS. Eighteen patients (10 men; age, 57 ± 16 years, mean ± SD) with proliferative retinopathy secondary to diabetes (n = 13) and ischemic retinal vein occlusion (n = 5) with no previous PRP therapy were studied. Blood samples were obtained before and at 4 months after the last PRP session. Baseline (prelaser) plasma levels of VEGF, sFlt-1, and vWf (all by ELISA) were compared with levels in 16 diabetic patients with background retinopathy ("hospital controls"), and 18 healthy, age- and sex-matched "healthy controls."

RESULTS. Patients with proliferative retinopathy had significantly raised plasma VEGF when compared with both control groups (P = 0.001). Patients with proliferative retinopathy and hospital controls had significantly raised plasma vWf levels when compared with healthy controls (P = 0.012). There was no difference in sFlt-1 levels between patients and controls (P = 0.162). After PRP, there was a significant reduction in plasma VEGF levels at 4 months’ follow-up (P < 0.001), but no significant changes in plasma sFlt-1 or vWf levels. Patients with complete resolution of neovascularization had a trend toward lower median VEGF levels (80 versus 150 pg/ml, P = 0.062), but vWf levels (P = 0.50) and sFlt-1 (P = 0.479) were not statistically different. Baseline VEGF and sFlt-1 levels were significantly correlated (Spearman r = 0.505, P = 0.032) but after PRP at 4 months’ follow-up, this was no longer significant (r = -0.269, P = 0.28).

CONCLUSIONS. In this pilot study, patients with proliferative retinopathy demonstrate elevated peripheral markers of angiogenesis and endothelial dysfunction, suggesting a role for these processes in the pathogenesis of this condition. A fall in levels of VEGF after successful laser treatment may provide an opportunity for monitoring disease progression or relapse via a blood sample.

	Introduction

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Severe visual impairment associated with diabetic retinopathy is primarily a sequel of retinal neovascularization leading to vitreous hemorrhage and/or tractional retinal detachment, or of diabetic maculopathy. In the retinas of individuals with diabetes, some of the earliest pathophysiological changes include selective loss of capillary pericytes, impairment of retinal vascular autoregulation, and the failure of the capillary circulation, resulting in regions of retinal nonperfusion. These changes subsequently lead to increased retinal vascular permeability, chronic retinal hypoxia, and extensive retinal ischemia, eventually resulting in retinal neovascularization. These processes are thought to be mediated by various growth factors, such as vascular endothelial growth factor (VEGF).^{1 2}

VEGF is a potent, secreted growth factor that promotes angiogenesis.³ In the eye, numerous types of retinal cells are recognized to produce VEGF, including retinal pigment epithelial cells, pericytes, endothelial cells, Müller cells, and astrocytes.^{1 4} Intraocular VEGF levels have also been studied in animal models and human vitreous fluid, where the levels are found to be high in patients with active intraocular neovascularization, such as proliferative diabetic retinopathy, ischemic central retinal vein occlusion, rubeosis iridis, and retinopathy of prematurity.⁵ Changes in intraocular VEGF levels have also been related to effective laser treatment.⁵

VEGF interacts with endothelial cells via two high-affinity membrane-spanning receptors, Flt-1 and KDR. The role of Flt-1 in embryonic vasculogenesis and adult angiogenesis and its association with several diseases have been clearly established.⁶ The presence of these two receptors has also been identified on retinal endothelial cells and pericytes.⁷ A soluble form of Flt-1 (sFlt-1) has been identified in conditioned culture media of human umbilical vein endothelial cells,⁸ although the pathophysiological importance of this is uncertain. Nevertheless, in the clinical setting sFlt-1 has not been previously measured in plasma and related to corresponding VEGF levels or therapy.

We hypothesized that subjects with proliferative retinopathy would have detectable raised levels of plasma VEGF, suggesting angiogenesis, and vWf, indicating endothelial damage or dysfunction.⁹ We also investigated the relationship between plasma VEGF and the status of retinal neovascularization and its changes after pan-retinal photocoagulation (PRP). To improve our understanding of VEGF, we also measured corresponding levels of the peripheral soluble VEGF receptor, sFlt-1.

	Materials and Methods

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We recruited patients with proliferative retinopathy secondary to diabetes and ischemic central retinal vein occlusion with no previous PRP therapy. The diagnosis of diabetic retinopathy was made with retinal photographs and on slit-lamp biomicroscopy with the aid of fluorescein angiography in doubtful cases, using the modified Airlie House criteria to classify diabetic retinopathy as none, background, preproliferative, and proliferative^{10 11} ; only patients with background and proliferative retinopathy were recruited for this pilot study. Patients with diabetes were diagnosed based on standard World Health Organization criteria, and all had to be attending our specialist diabetes clinic.¹¹ All patients with proliferative diabetic retinopathy had been referred for PRP therapy in view of obvious neovascularization. The diagnosis of branch retinal vein occlusion had previously been made clinically by the presence of classical fundoscopic appearances in the distribution of the obstructed branch retinal vein and confirmed from fluorescein angiography.¹² The diagnosis of ischemic central retinal vein occlusion had previously been made on clinical grounds by the presence of relative afferent pupillary defect, with or without rubeosis, and classical fundoscopic appearances of retinal hemorrhages and dilated tortuous veins in all four quadrants.¹² All patients with branch and central retinal vein occlusion who were considered for the present study had clear evidence of retinal neovascularization. The project had the approval of the Ethics Committee of West Birmingham Health Authority.

After informed consent, blood samples were obtained before and at 4 months after the last PRP session, for plasma VEGF, sFlt-1, and vWf levels, as well as glycated hemoglobin (HbA1c), as an index of diabetes control. Baseline (prelaser) plasma VEGF, sFlt-1, and vWf levels in patients with proliferative retinopathy were compared with levels in the following: (1) diabetic patients with minimal background retinopathy ("hospital controls"); and (2) age- and sex- matched healthy control subjects recruited from those attending hospital for nonacute minor surgical conditions, such as cataract surgery, varicose veins, and hernia surgery, and from members of the hospital staff. None of the patients or healthy controls had a history of renal or liver disease, malignancy, connective tissue disease, deep vein thrombosis, or pulmonary embolism.

Laboratory Assays
VEGF levels were measured by ELISA: 0.4 µg/ml anti-VEGF₁₆₅ (R&D Systems, Abingdon, UK) in 0.05 M carbonate buffer, pH 9.6, was adsorbed onto 96-well plates (Dynatech Laboratories, Sussex, UK) for at least 15 hours at 4°C (100 µl/well). The plates were washed five times in 0.1 M PBS, pH 7.2, supplemented with 0.05% Tween 20 (PBS-T) before and after blocking for 2 hours at room temperature (RT) with 5% dried powdered milk (Marvel in PBS-T). Subsequently 100 µl of triplet rhVEGF standards (R&D Systems) diluted in wash buffer [ranging from 10 pg/ml to 250 ng/ml and blank (assay buffer)] or plasma was added to each well. After incubation for 2 hours at RT and five washes as before, 100 µl biotinylated goat anti-human VEGF (500 µg/ml in assay buffer; R&D Systems) was then added to each well, and plates were left for a further 2 hours at RT. After washing, 100 µl of Extravidin-peroxidase (Sigma-Aldrich, Poole, Dorset) at 1:1000 dilution was added, and plates incubated at RT for 45 minutes. The plates were washed five times, and substrate [o-phenylenediamine dihydrochloride in 0.05 M citrate buffer, pH 5, with hydrogen peroxide (Sigma-Aldrich)] was added to allow color development. The reaction was stopped using 3 M HCl (Sigma-Aldrich), and the absorbance was read immediately in an ELISA reader at 492 nm. The assay has a minimum sensitivity of 15 pg/ml, with an intra-assay coefficient of variation of 4.9% (n = 18) and an interassay coefficient of variation of 9.1% (n = 20) at 1.6 ng/ml.

Level of sFlt-1 able to bind immobilized VEGF were measured in a modified ELISA: 0.4 µg/ml rabbit polyclonal anti-VEGF (R&D Systems) in 0.05 M carbonate buffer, pH 9.6, was adsorbed onto 96-well plates (Dynatech Laboratories) for at least 15 hours at 4°C (100 µl/well). The plates were washed and blocked as previously described, saturated with 100 µl/well of 250 ng/ml rhVEGF (R&D Systems), and left at RT for 2 hours. Plates were washed, and 100 µl of triplet rhFlt-1/Fc chimera (R&D Systems) standards diluted in wash buffer [ranging from 100 pg/ml to 500 ng/ml and blank (assay buffer)] or plasma was added to each well. Plates were incubated for an additional 2 hours at RT and then washed as before. One hundred microliters of biotinylated goat anti-human Flt-1 (500 µg/ml in assay buffer; R&D Systems) was added to each well, and plates were left for another 2 hours at RT. The assay was completed with extravidin-peroxidase, substrate, and hydrochloric acid and read at 492 nm as described above. This assay has a lower limit of sensitivity of 50 pg/ml, an intra-assay coefficient of variation of 3.7% (n = 12), and an interassay coefficient of variation of 8.8% (n = 18) at 10 ng/ml. Levels of vWf were determined using an established ELISA¹³ with reagents from Dako (Ely, UK). HbA1c was measured in diabetic patients using a standard high-pressure liquid chromatography method in our routine clinical chemistry laboratory, which is based on ion exchange chromatography principles.¹⁴ Erythrocyte hemolysates were passed through a MonoS ion exchange column (Pharmacia, Uppsala, Sweden), where the charge is altered by passing an increasing gradient of lithium chloride through the column, thus promoting the elution of the hemoglobin fractions from the column. Fractions of HbA1c are detected by measuring the absorption of light of the different fractions at 415 nm using a Thermoquest Spectra system (Thermoquest, Manchester, UK), and the concentration of each fraction is directional proportional to the absorbance at 415 nm. The proportion of HbA1c is calculated as the ratio of the area of the HbA1c peak to the sum of the areas of the HbA1c and HbA peaks.

Power Calculations and Statistical Analysis
We calculated that 18 patients and 18 controls would have 90% power at the P < 0.01 significance level to detect a change of 1 SD in VEGF levels. Because data for VEGF, sFlt-1, and vWf are nonparametrically distributed, they are presented as median [interquartile range (IQR)]. Differences between patients, hospital controls, and healthy controls were compared using the one-way analysis of variance (ANOVA) or Kruskal-Wallis test as appropriate, whereas paired comparisons between levels at baseline and 4 months’ postlaser were compared using the paired Wilcoxon test. Data for HbA1c are presented as mean ± SD and analyzed using the unpaired t-test for comparisons between cases and hospital controls and the paired t-test for sequential changes. Spearman’s rank correlation was used to relate levels of VEGF to sFlt-1. Data were entered onto a computerized database, and statistical calculations were performed on a microcomputer using a commercially available statistical package (Minitab version 12 for Windows; Minitab Inc, State College, PA). A value of P < 0.05 was considered significant in all statistical analyses.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
We studied 18 patients (10 men; age, 57 ± 16 years, mean ± SD) with proliferative retinopathy secondary to diabetes (n = 13, with 9 receiving insulin) or ischemic retinal vein occlusion (n = 5, all nondiabetic with branch retinal vein occlusion in 3 and central retinal vein occlusion in 2 with no previous PRP therapy.

When these patients were compared with 16 hospital controls (i.e., diabetic patients with only background retinopathy; mean age, 64 years) and age- and sex-matched healthy controls (mean age, 56 years), there were significantly elevations of plasma VEGF (Kruskal-Wallis test, P = 0.001). Patients with proliferative retinopathy and hospital controls had significantly raised plasma vWf levels when compared with healthy controls (P = 0.012; Table 1 ). There was no significant difference in sFlt-1 levels in between patients and controls (P = 0.162). There was no statistically significant difference in mean age (one-way ANOVA P = 0.184) between the three groups studied, nor was there a significant difference in mean HbA1c levels between patients with proliferative retinopathy and hospital controls (unpaired t-test, P = 0.14).

View larger version (13K): [in this window] [in a new window]   Figure 1. Figute 1. VEGF levels in peripheral retinopathy: effects of laser photocoagulation.

Correlations
Baseline VEGF and sFlt-1 levels in patients with proliferative retinopathy were significantly correlated (Spearman r = 0.505, P = 0.032), but there were no significant correlations between other baseline variables. After PRP and 4 months’ follow-up, there was no longer a significant correlation between VEGF and sFlt-1 levels (r = -0.269, P = 0.28).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
High VEGF mRNA in retinal sections¹⁵ and plasma vWf^{16 17} levels have previously been noted in diabetics with proliferative retinopathy and ischemic central retinal vein occlusion. Two studies failed to find significant relationships between serum VEGF levels and stage of retinopathy, although aqueous levels were significantly different^{18 19} ; nevertheless, the use of serum to measure systemic VEGF levels has to be interpreted with caution, because activated platelets (during blood clotting) release VEGF into serum, and thus, results based on serum samples may be inaccurate in view of the possible artifact relating to the source of VEGF levels.²⁰ The present study avoids this problem by measurement of VEGF levels from citrated plasma. Importantly, we are not aware of previous reports on (1) plasma sFlt-1 levels in proliferative retinopathy; and (2) the effects of laser treatment.

The present study has demonstrated high plasma VEGF levels, in keeping with an angiogenic state, in patients with untreated proliferative retinopathy. Despite previous studies demonstrating upregulation of VEGF in retinas from patients with diabetes but with no retinopathy,¹⁵ the raised plasma VEGF levels in the present study cannot simply be explained by diabetes alone, because median VEGF levels were twofold higher in the patients with proliferative retinopathy than in patients with diabetes with no proliferative retinopathy who also had broadly comparable glycemic control, with no significant difference in mean HbA1c levels. Indeed, median VEGF levels in the hospital controls were intermediate between that seen in healthy controls and the patients with proliferative retinopathy, and laser therapy significantly reduced VEGF levels in the patients with proliferative retinopathy to levels even lower than that seen in the hospital controls. Nevertheless, we did not quantify the total number or intensity of laser burns in the patients with proliferative retinopathy, because clinical practice in our unit was to apply laser treatment to the peripheral retina until regression of neovascularization at follow-up or if all the accessible peripheral retinal area had been ablated. Furthermore, the quantity of laser treatment as well as the parameters applied was variable between and within clinicians and patients.

Although the high VEGF levels may in part be related to endothelial activation, damage, or dysfunction, as evident by raised baseline vWf levels,⁹ although levels failed to correlate with those of VEGF. Levels of vWf were not changed by the laser treatment, suggesting that the source of this increase is extraocular and is probably systemic, reflecting more general-ized vascular dysfunction in diabetes.^{9 .16} In contrast to the highly elevated levels of VEGF (seven times normal), levels of its soluble receptor, sFlt-1, were only marginally raised, suggesting little pathophysiological significance under these conditions.

There was a marked reduction in VEGF levels after pan-retinal photocoagulation. Importantly, sFlt-1 levels at follow-up remained unchanged from baseline, and there was no longer any significant correlation between follow-up levels of VEGF and sFlt-1. This suggests that the angiogenic stimuli responsible for increased VEGF appears to have decreased, but the factors influencing sFLT-1 cleavage/shedding from the endothelium still remain unaltered. Notably, levels of VEGF fell despite the presence of an approximate 500-fold excess in levels of its soluble receptor.

The ease of measurement of plasma VEGF and sFlt-1 levels in diabetic patients with proliferative retinopathy may possibly serve as predictors of effectiveness of laser treatment, as demonstrated by our study. Indeed, our subgroup analysis also suggested a trend toward lower VEGF levels in the patients with complete resolution of neovascularization when compared with those with partial resolution, although there is limited power for this comparison. Thus, changes in plasma VEGF levels may provide a quick, easy, and convenient opportunity for monitoring disease progression or relapse using a blood sample, which would be of great interest to nonophthalmologists and general practitioners. The high plasma sFlt-1 levels would also have implications for attempts at therapeutic VEGF-receptor blockade, because administered therapy would have to "neutralize" circulating VEGF receptors before adequate levels at VEGF receptors on target organs would be achieved.

In conclusion, this pilot study of patients with proliferative retinopathy has demonstrated elevated peripheral (plasma) markers of angiogenesis and endothelial dysfunction, suggesting a role for these processes in the pathogenesis of this condition. A decrease in levels of VEGF after successful laser treatment may provide an opportunity for monitoring disease progression or relapse via a blood sample.

	Footnotes

 
Supported by the City Hospital Research and Development Program for the Haemostasis, Thrombosis, and Vascular Biology Unit and by a research fellowship from the Birmingham Eye Foundation (PLL).

Submitted for publication September 1, 1999; revised November 30, 1999 and February 2, 2000; accepted February 15, 2000.

Commercial relationships policy: N.

Corresponding author: Gregory Y. H. Lip, University Department of Medicine, City Hospital, Dudley Road, Birmingham B18 7QH, UK. g.y.h.lip{at}bham.ac.uk

	References

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