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Mediation of Systemic Vascular Hyperpermeability in Severe Psoriasis by Circulating Vascular Endothelial Growth Factor
Daniel Creamer, MBBChir, MRCP;
Michael Allen, MPhil;
Rhys Jaggar, PhD;
Richard Stevens, MBBS, MRCP;
Roy Bicknell, DPhil;
Jonathan Barker, MD
Arch Dermatol. 2002;138:791-796.
ABSTRACT
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Background Severe forms of psoriasis can be complicated by systemic microvascular
hyperpermeability. Vascular endothelial growth factor (VEGF) possesses potent
vascular permeability activity. We suggest that VEGF enters the systemic circulation
and acts on microvessels to mediate hyperpermeability.
Objectives To quantify renal microvascular permeability and circulating VEGF concentration
in severe psoriasis, and to investigate the relationship between plasma VEGF
concentration and skin and joint involvement.
Design Inception cohort studies of patients with generalized pustular psoriasis
and plaque psoriasis.
Setting St John's Institute of Dermatology, London, England.
Patients Twenty-two patients (15 men and 7 women) with moderate and severe psoriasis
were recruited (age range, 29-77 years; mean age, 47 years); 5 had generalized
pustular psoriasis, 2 had erythrodermic psoriasis, and 15 had moderate-severe
plaque psoriasis. An age- and sex-matched control group of 17 individuals
(10 men and 7 women) was recruited (age range, 29-69 years; mean age, 42 years).
Results There was pathological proteinuria in patients with relapsing generalized
pustular psoriasis, (4-fold increase in urinary protein excretion rate in
relapse compared with remission). In patients with moderate and severe psoriasis,
mean plasma VEGF concentration during relapse was approximately 2.5 times
greater than during remission (mean VEGFrelapse = 257 pg/mL; mean
VEGFremission = 103 pg/mL; P<.01).
There was a correlation between extent of skin involvement and plasma VEGF
level (mean VEGFsevere psoriasis = 365 pg/mL; mean VEGFmoderate
psoriasis = 149 pg/mL; P = .03). There was
a correlation between presence of psoriatic arthritis and plasma VEGF level
(mean relapse VEGFarthritis = 277 pg/mL; mean relapse VEGFnonarthritis = 103.5 pg/mL; P = .03).
Conclusions Generalized pustular psoriasis is accompanied by pathological proteinuria
and elevated plasma VEGF levels. Plasma VEGF concentration is significantly
elevated in patients with extensive skin and joint involvement and may act
on renal microvasculature to induce hyperpermeability.
INTRODUCTION
PSORIASIS IS A common, chronic skin disease characterized by hyperproliferation
of the epidermis, inflammatory cell accumulation, and elongation and exaggerated
tortuosity of cutaneous blood vessels.1-2
Evidence3-4 suggests that expansion
of the superficial dermal microvascular plexus in psoriasis is mediated by
an active vasoproliferative process known as angiogenesis. Under physiological
conditions, angiogenesis occurs in the endometrial cycle and during wound
healing, whereas pathological angiogenesis is important in tumor growth and
metastasis, atherosclerosis, and certain inflammatory conditions, such as
rheumatoid arthritis.5 Vascular proliferation
in angiogenesis is driven by the local expression of angiogenic factors6 and in psoriasis studies7-13
have demonstrated overexpression by lesional skin of several angiogenic peptides,
including tumor necrosis factor  , transforming growth factor ,
interleukin 8, thymidine phosphorylase, endothelial cell–stimulating
angiogenesis factor, angiopoietin, and vascular endothelial growth factor
(VEGF).
Vascular endothelial growth factor was originally identified as a tumor
cell–derived factor that induced microvascular hyperpermeability and
was therefore initially termed vascular permeability factor.14 Subsequent studies15
characterized VEGF as an endothelial cell–specific mitogen. Vascular
endothelial growth factor is recognized as a central regulator of angiogenesis
because endothelial proliferation and microvascular hyperpermeability are
critical early steps in the angiogenesis pathway.16
Results of clinical studies17 have suggested
that high levels of circulating VEGF may induce systemic microvascular hyperpermeability
in situations characterized by widespread capillary leak, such as the ovarian
hyperstimulation syndrome. In patients with extensive, active psoriasis, systemic
disturbance is not uncommon; fever, fluid imbalance, and thermoregulatory
dysfunction are recognized complications. In chronic plaque psoriasis, microalbuminuria
indicates subclinical renal microvascular hyperpermeability,18
whereas further studies19 have demonstrated
that the extent of albuminuria reflects the degree of psoriatic skin involvement.
Microalbuminuria in psoriasis may result from the activity of a circulating
permeability factor produced by lesional tissue. Following our reported20 observation of elevated plasma VEGF in erythrodermic
psoriasis, we hypothesize that in severe psoriasis, VEGF, elaborated by lesional
psoriatic tissue, enters the systemic circulation and acts in an endocrine
fashion on renal microvasculature to induce clinically significant hyperpermeability.
There are several reports21-22
of severe pulmonary edema occurring in patients with generalized pustular
psoriasis (GPP), the edema accumulating as a direct consequence of increased
pulmonary microvascular permeability. Hypoalbuminemia is a common complication
of GPP, and this association may again reflect microvascular hyperpermeability
with protein loss into the gastrointestinal or renal tracts. In the present
study, renal microvascular permeability and circulating VEGF have been quantified
in patients with GPP during relapse and remission. In a larger group of patients
with moderate and severe psoriasis, correlation has been sought between the
extent of skin involvement and plasma VEGF concentration and between the presence
of psoriatic arthritis and plasma VEGF concentration. Lesional skin and joint
fluid has been assayed to identify the source of circulating VEGF in psoriasis.
PATIENTS, MATERIALS, AND METHODS
PATIENTS
Patients participated in this study after regional and hospital ethics
committee approval had been obtained. Of the 22 patients (15 men and 7 women;
age range, 29-77 years; mean age, 47 years) with active psoriasis in this
study, 5 had GPP, 2 had erythrodermic psoriasis, and 15 had moderate-severe
plaque psoriasis (Table 1). Psoriasis
Area and Severity Index (PASI) scoring was used to assess disease activity
in patients with plaque psoriasis and in those with GPP in remission.23 For purposes of comparison, severe psoriasis was
defined as GPP or plaque disease with a PASI score greater than 30, whereas
moderate psoriasis was defined as plaque disease with a PASI score less than
30. Ten of 22 patients had active psoriatic arthritis at the time of relapse
of their skin disease. Patients were classified as having active arthritis
if they had morning stiffness for more than 45 minutes, 5 swollen joints,
and 5 tender joints.24 Venous blood samples
were taken from all 22 patients for VEGF analysis during relapse and remission.
Blood samples were taken from premenopausal women at times outside menstruation.
Urine specimens were taken from patients with GPP for protein analysis during
relapse and remission. Relapse was defined as a flare of disease activity
characterized by a PASI score increase greater than 70%, and remission was
defined as a nadir of disease activity after treatment characterized by a
PASI score decrease greater than 70%.
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Table 1. Plasma VEGF Concentrations and PASI Scores in 22 Patients
With Psoriasis During Relapse and Remission*
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A control group of 17 individuals (10 men and 7 women; age range, 29-69
years; mean age, 42 years) was recruited. Venous blood samples were obtained
from each control for VEGF analysis. Again, in premenopausal women, blood
samples were obtained at times outside menstruation.
A separate group of 8 patients (5 men and 3 women; age range, 24-69
years; mean age, 42 years) with active psoriatic arthritis was enrolled, psoriatic
arthritis being defined according to the criteria of Moll and Wright.25 All patients had monoarthritis or oligoarthritis
with involvement of at least 1 knee joint. Synovial fluid samples for VEGF
analysis were obtained from knee joints displaying clinical signs of active
synovitis (Table 2).
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Table 2. Clinical Details and Synovial VEGF Concentrations in 8 Patients
With Psoriatic Arthritis*
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For RNA experiments, two 6-mm punch biopsy samples were taken from active
plaques in 4 patients. Treatment was limited to emollients alone in the 2
weeks preceding biopsy. Normal skin tissue for RNA extraction was obtained
from operative mammoplasty procedures (n = 3).
URINARY PROTEIN EXCRETION
Urinary protein excretion rates (UPERs) in 5 patients with GPP were
quantified in relapse and remission. Timed 24-hour samples were collected,
and protein was assayed using a dye-binding colorimetric method (Biotrol Urine
Proteins; Diagnostics Merck-Biotrol, Nogent-sur-Marne, France). The assay
uses a molybdate–pyrogallol red complex that reacts with protein in
acidic solution to form a blue-purple complex that absorbs at 600 nm.26 The color intensity measured at 600 nm is directly
proportional to the protein concentration in the sample.
VEGF ENZYME-LINKED IMMUNOSORBENT ASSAY
Venous blood samples were immediately anticoagulated with sodium heparin,
10 U/mL, in sterile, endotoxin-free tubes and centrifuged at 400g for 10 minutes, supernatant removed, and stored at –70°C
until required. Synovial fluid from knee effusions was drained using a sterile
technique, and samples were separated, as indicated for venous blood samples,
into a cellular and supernatant fraction. The 100-µL samples of plasma
and synovial fluid were immunoassayed in duplicate for human VEGF using a
commercially available quantitative enzyme-linked immunosorbent assay kit
that measures VEGF165 (Quantikine; R & D Systems, Oxford, England).
Although all 4 VEGF species have biological activity, VEGF165 is
soluble compared with VEGF189 and VEGF206, which remain
cell associated and, therefore, of relevance in this study. The Quantikine
kit uses a quantitative sandwich enzyme immunoassay method and has a minimum
level of detection of 9 pg/mL.
RNA PREPARATION AND RIBOPROBE CONSTRUCTION
Psoriatic and normal skin specimens were homogenized using a manual
microhomogenizer. The RNA was prepared using a method adapted from Chomczynski
and Sacchi.27 A VEGF riboprobe was designed
to protect the full length of the smallest isoform (VEGF121, yielding
a 471-base band, with a lower band of 427 bases representing the remaining
isoforms). This 520-base probe was generated by linearizing the full-length
complementary DNA for VEGF121 (including 26 bp of 3' untranslated
sequence) cloned into pBluescript SK with EcoRV and transcribed with T7RNA
polymerase.
RIBONUCLEASE PROTECTION ANALYSIS
A minimum of 100 000 cpm of each antisense riboprobe was hybridized
overnight at 55°C to each sample with transfer RNA as a negative control.
The RNase digestion of the unhybridized RNA fragments was achieved by adding
RNase digestion buffer containing RNases A and T1 to each sample. RNases were
inactivated with 12.5 µL of a mixture containing 16% sodium dodecylsulphate
solution with proteinase K, 4 µg/µL. After phenol extraction and
ethanol precipitation, the samples were resuspended and loaded onto 5% polyacrylamide/urea
sequencing gels followed by autoradiography.28
In each hybridization, an antisense transcript corresponding to human DNA
topoisomerase transcribed from a construct was included as an internal control.
Positive control messenger RNA from a breast carcinoma was loaded onto each
gel. The resulting bands were quantitated densitometrically using a standard
Gel Plotting macro and a software program (NIH Image 1.61; National Institutes
of Health, Bethesda, Md). Vascular endothelial growth factor signals were
normalized to the internal control (DNA topoisomerase).
RESULTS
URINARY PROTEIN EXCRETION RATES
All 5 patients with GPP demonstrated pathological UPERs during relapse
(range, 0.15-1.59 g/24 h; mean, 0.55 g/24 h; reference value, <0.15 g/24
h). During remission, 4 of 5 UPER values returned to within reference values
(range, 0.09-0.20 g/24 h; mean, 0.14 g/24 h; reference value, <0.15 g/24
h) (Figure 1). There was a mean
4-fold increase in UPER in relapse compared with remission.
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Figure 1. Urinary protein excretion rate
(UPER) in 5 patients with generalized pustular psoriasis during relapse and
remission.
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PLASMA VEGF ANALYSIS
The 5 patients with GPP demonstrated mean plasma VEGF levels 2.6-fold
greater in relapse compared with remission (Figure 2). In the larger group of 22 patients (5 with GPP, 2 with
erythrodermic psoriasis, and 15 with moderate-severe plaque psoriasis), mean
plasma VEGFrelapse concentration was approximately 2.5 times greater
than VEGFremission (mean ± SEM VEGFrelapse =
257 ± 49 pg/mL and VEGFremission = 103 ± 6.7 pg/mL; P<.01, 2-sample t test) (Figure 3). Plasma VEGF concentration in an
age- and sex-matched control group (n = 17) was significantly lower than VEGFrelapse and VEGFremission (mean ± SEM VEGFremission = 103 ± 6.7 pg/mL, VEGFcontrol = 24.7 ± 6.7
pg/mL; P<.001, 2-sample t
test) (Figure 3).
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Figure 2. Plasma vascular endothelial growth
factor (VEGF) concentration in 5 patients with generalized pustular psoriasis
during relapse and remission.
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Figure 3. Mean plasma vascular endothelial
growth factor (VEGF) concentration in 22 patients with psoriasis (5 with generalized
pustular psoriasis, 2 with erythrodermic psoriasis, and 15 with moderate-severe
plaque psoriasis) during relapse and remission vs 17 age- and sex-matched
controls. Error bars represent SEM.
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Comparison of plasma VEGF levels in patients with severe psoriasis (GPP
+ PASI score >30) (n = 11) vs those with moderate psoriasis (PASI score <30)
(n = 11) demonstrated significantly higher VEGF levels in the severe group
(mean ± SEM VEGFsevere = 365 ± 78 pg/mL, VEGFmoderate = 149 ± 43 pg/mL; P = .03,
2-sample t test) (Figure 4).
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Figure 4. Comparison of mean plasma vascular
endothelial growth factor (VEGF) levels in patients with severe psoriasis
(generalized pustular psoriasis and Psoriasis Area and Severity Index [PASI]
score >30) (n = 11) vs patients with moderate psoriasis (PASI score <30)
(n = 11). Error bars represent SEM.
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A relationship was demonstrated between circulating VEGF levels and
the presence of active psoriatic arthritis (mean ± SEM relapse VEGFarthritis = 277 ± 53 pg/mL [n = 10], mean relapse VEGFnonarthritis = 103.5 ± 19.0 pg/mL [n = 12]; P =
.03, 2-sample t test) (Figure 5).
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Figure 5. Comparison of mean plasma vascular
endothelial growth factor (VEGF) levels in patients with psoriasis and active
arthritis (n = 10) vs those with psoriasis without arthritis (n = 12) during
disease relapse. Error bars represent SEM.
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PSORIATIC SYNOVIAL FLUID VEGF ANALYSIS
In another group of 8 patients with active psoriatic arthritis, synovial
fluid VEGF was assayed using enzyme-linked immunosorbent assay (Table 2). The VEGF enzyme-linked immunosorbent assay has a minimum
level of detection for VEGF165 of 9 pg/mL. High synovial VEGF concentrations
(mean ± SEM, 1972 ± 221.1 pg/mL) were identified in each case.
RIBONUCLEASE PROTECTION ANALYSIS
Ribonuclease protection assays for VEGF are shown in Figure 6. Short (48-hour) exposure demonstrated a strong signal
for VEGF in all 4 psoriasis samples. In normal skin (n = 3) at the same exposure,
VEGF signals are of low intensity. To obtain values of fold-change in messenger
RNA levels, messenger RNA abundance was quantitated from autoradiographic
data by scanning laser densitometry. Signals from the VEGF messenger RNA were
normalized to those of the internal topoisomerase control. Quantification
by this method showed an approximate 4-fold increase in VEGF signal in lesional
vs normal skin.
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Figure 6. Ribonuclease protection assays
for vascular endothelial growth factor (VEGF) messenger RNA from lesional
psoriatic skin (n = 4) and normal nonpsoriatic skin (n = 3). Control messenger
RNA was from a breast carcinoma sample. The internal control is DNA topoisomerase
(TOPO).
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COMMENT
Our findings demonstrate that GPP is accompanied by pathological proteinuria
and markedly elevated concentrations of plasma VEGF. During remission, urinary
protein excretion normalizes and circulating VEGF levels return to control
values. In a larger group of patients (including those with GPP, erythrodermic
psoriasis, and plaque psoriasis), plasma VEGF concentration is consistently
higher in relapse than in remission and is significantly elevated in patients
with extensive skin involvement and active joint disease. We suggest that
VEGF, synthesized in psoriatic skin and synovium, enters the systemic circulation
and may act on renal microvasculature to induce hyperpermeability with consequent
proteinuria.
Renal microvascular hyperpermeability permits the escape of larger protein
molecules and those of smaller molecular weight (eg, albumin), which pass
into the glomerular filtrate and are clinically measurable as proteinuria.
Microalbuminuria, defined as mildly elevated levels of proteinuria (30-200
mg/L), has been reported in patients with mild-moderate psoriasis by Cecchi
et al.19 The mean UPER in their cohort of patients
with a PASI score greater than 11 was 28.8 mg/24 h, whereas the mean relapse
UPER in our GPP group was 560 mg/24 h, which reduced to 140 mg/24 h during
remission (reference value, <150 mg/24 h). The results of Cecchi and colleagues
and our own data suggest the presence of renal microvascular hyperpermeability
in psoriasis that increases with intensity of skin disease but reverses with
successful treatment.
Within the papillary dermis of lesional, psoriatic skin, the superficial
microvasculature is characterized by an angiogenic and hyperpermeable phenotype,
features that contribute to the development and persistence of skin lesions
in psoriasis. Microvascular hyperpermeability at any site can be mediated
by several biologically active substances, including VEGF, which has permeability
activity 40 000 times greater than histamine on a molar basis.29 Detmar et al13 initially
identified VEGF overproduction in psoriatic epidermis, and they30
subsequently demonstrated the central role of keratinocyte-derived VEGF in
changes to underlying superficial dermal microvasculature. In addition to
acting locally to induce angiogenesis and microvascular hyperpermeability,
circulating VEGF has been implicated in systemic capillary permeability associated
with conditions such as ovarian hyperstimulation syndrome and tumor ascites.17, 31 Other studies have demonstrated up-regulation
of VEGF in pathological conditions characterized by proteinuria and increased
renal microvascular permeability.32
Bhushan et al11 reported an association
among VEGF concentration in lesional skin, extent of psoriatic skin involvement
(PASI), and VEGF concentration in peripheral blood. In our experiments, the
finding that patients with severe psoriasis (GPP + PASI score >30) had significantly
higher levels of plasma VEGF compared with patients with moderate psoriasis
(PASI score <30) again suggests that circulating levels of VEGF reflect
the extent of psoriatic skin involvement. Further evaluation revealed that
patients with active psoriatic arthritis had significantly higher levels of
circulating VEGF than those without arthropathy, whereas separate experiments
demonstrated high concentrations of VEGF in the articular fluid of involved
psoriatic joints. High synovial VEGF concentrations in psoriatic synovial
fluid were initially reported by Fearon et al,33
and our results are consistent with their data. These findings indicate that
an articular source may contribute, along with the cutaneous source, to circulating
VEGF concentration in patients with active psoriasis.
We hypothesize that there may be a causal relationship between renal
microvascular hyperpermeability in patients with severe psoriasis and high
circulating VEGF levels. Reports of pulmonary edema in GPP secondary to the
capillary leak syndrome suggest the involvement of pulmonary microvascular
hyperpermeability, which may be mediated by a circulating vasoactive cytokine,
such as VEGF.16-17 Although the
renal and pulmonary vasculature can respond to circulating permeability signals
in severe psoriasis, other microvascular beds seem to be resistant to systemic
hyperpermeability factors. Organ-dependent variations in response to VEGF
may be explained by a lack of accessibility of bioactive VEGF in certain sites
or because of qualitative or quantitative differences in VEGF receptors.
Plasma VEGF analysis in patients with severe psoriasis may be a useful
predictor of clinical outcome and affect management. In addition, VEGF and
VEGF-mediated pathways may represent potential targets in the development
of future therapeutic strategies in psoriasis.
AUTHOR INFORMATION
Accepted for publication August 7, 2001.
This research was supported by the Special Trustees of St Thomas' Hospital
(Dr Creamer) and by Smith's Charity, London.
Corresponding author and reprints: Daniel Creamer, MB,BChir, MRCP,
Department of Dermatology, King's College Hospital, Denmark Hill, London SE5
9RS, England (e-mail: daniel.creamer{at}kingshc.nhs.uk).
From St John's Institute of Dermatology, St Thomas' Hospital, King's
College Hospital, London, England (Drs Creamer and Barker and Mr Allen); the
Molecular Angiogenesis Group, Imperial Cancer Research Fund, Institute of
Molecular Medicine, Oxford, England (Drs Jaggar and Bicknell); and the Department
of Rheumatology, St Thomas' Hospital, London (Dr Stevens).
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