Clinical Rheumatology

, Volume 24, Issue 2, pp 111–116 | Cite as

Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement

  • Anna Kuryliszyn-Moskal
  • Piotr Adrian Klimiuk
  • Stanislaw Sierakowski
Original Article

Abstract

Systemic sclerosis (SSc) is a chronic, multisystemic, autoimmune disease characterised by vascular changes and varying degrees of fibrosis of the skin and visceral organs. Organ systemic involvement in SSc is associated with an altered function of endothelial cells, perivascular infiltrating mononuclear cells and interstitial fibrosis. To evaluate the relationship between systemic manifestations and immunological markers of endothelial cell activation, serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were determined by an enzyme-linked immunosorbent assay in 31 SSc patients and in 30 healthy controls. In comparison with the control group, higher serum concentrations of sVCAM-1, sE-selectin, VEGF and ET-1 were detected in SSc patients (in all cases p<0.001). Elevated concentrations of sVCAM-1 (p<0.05), sE-selectin (p<0.05), VEGF (p<0.05) and ET-1 (p<0.01) dominated in the serum of SSc patients with organ systemic involvement compared to those without systemic manifestation of the disease. These results suggest that the serum levels of sVCAM-1, sE-selectin, VEGF and ET-1 may reflect the extent of internal organ involvement in SSc patients and point to a pathogenic role of these molecules in systemic manifestation of the disease.

Keywords

sE-selectin sET-1 sVCAM-1 Systemic sclerosis VEGF 

Abbreviations

ESR

Erythrocyte sedimentation rate

ET-1

Endothelin-1

RA

Rheumatoid arthritis

sE-selectin

Soluble E-selectin

SSc

Systemic sclerosis

sVCAM-1

Soluble vascular cell adhesion molecule-1

VEGF

Vascular endothelial growth factor

Introduction

Systemic sclerosis (SSc) is a chronic, multisystemic, autoimmune disease characterised by vascular changes and varying degrees of fibrosis of the skin and visceral organs. Although the pathogenesis of SSc is poorly understood, immunological, vascular and extracellular matrix protein abnormalities seem to play an essential role in the disease process. A broad spectrum of clinical presentations, ranging from relatively benign and limited (lSSc) to more severe and diffuse forms (dSSc) of the disease, is associated with a widespread disorder of the microvasculature, an altered function of endothelial cells, perivascular infiltrating mononuclear cells and interstitial fibrosis [1].

Autoimmune vascular damage resulting in endothelial cell injury, cytokine and adhesion molecule synthesis, followed by fibroblast activation and excessive tissue matrix protein production play a central role in the systemic manifestations of SSc [1]. The endothelium occupies a crucial position at the interface of the blood and the tissues and is involved in numerous mechanisms of the immune response such as the ability to present antigen to leucocytes and expression of adhesion molecules at the cell surface [2]. These adhesion molecules, which include vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, mediate the interactions between lymphocytes and vascular endothelial cells during extravasation and homing, allow local retention by adhesion to extracellular matrix and play an important role in costimulation of cellular activation [3]. Adhesion molecules have been detected as circulating soluble forms (sCAM) in the blood samples of patients with inflammatory and autoimmune rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), vasculitis and other inflammatory arthropathies [4, 5].

Inflammatory cell migration is also increased due to the stimulation of new blood vessel formation by endothelial growth factors [6]. Vascular endothelial growth factor (VEGF), as a fundamental modulator of angiogenesis, is involved in the pathogenesis of SSc and other fibrovascular disorders [7]. Clinical studies have documented elevations in the VEGF plasma levels in RA patients compared to healthy individuals [8, 9]. Moreover, it has been reported that high VEGF levels may be associated with the disease activity of RA [8].

Endothelin-1 (ET-1), released after activation and/or damage of endothelial cells, plays an important role in the fibrosing process as well as vasculopathy in connective tissue diseases [10]. Clinical studies have found higher levels of endothelin-1 in patients with SSc [11] compared with healthy controls. Furthermore, raised levels of ET-1 have been reported in patients with diffuse SSc (dSSc) compared with those with limited SSc (lSSc) and may be associated with endothelial cell damage [12].

Since the clinical course of SSc in an individual patient is unpredictable, tests capable of identifying those patients who will develop internal organ manifestation would be useful to rheumatologists. Some indicators have been reported to correlate with systemic manifestation and poor clinical outcome [13]. Therefore, the aim of this study was to investigate whether the levels of soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and of endothelin-1 (ET-1) are associated with the systemic involvement of SSc.

Patients and methods

Study groups

Thirty-one patients (31 women, mean age 55.2±10.4 years, mean disease duration 7.8±6.1 years) who gave their informed consent participated in the study. The disease duration was counted from the time when patients fulfilled the SSc criteria proposed by the American College of Rheumatology (ACR) [14]. All SSc patients were classified into two groups, those with internal organ involvement (16 cases) and those without any evidence of systemic manifestation in the course of SSc (15 persons). The group of 16 patients with systemic involvement included 13 patients with lung fibrosis on high-resolution computed tomography (HRCT) examination, 2 patients with pulmonary hypertension and 1 person with heart involvement (congestive heart failure). Among patients with systemic involvement oesophagus hypomotility was observed in five patients and in two cases heart arrhythmias were diagnosed.

Control sera were obtained from 30 healthy subjects, matched for sex and age.

Clinical and laboratory analysis

All patients were evaluated by extensive clinical and laboratory studies. Organ system involvement was defined as described [15]: lung—bibasilar pulmonary fibrosis on chest X-ray; isolated pulmonary hypertension—clinical evidence of pulmonary hypertension and increased mean pulmonary arterial pressure (>35 mmHg) by echocardiography, heart—pericarditis, congestive heart failure or arrhythmias requiring treatment; oesophagus—hypomotility shown by barium radiography; and joint—inflammatory polyarthralgias or arthritis. In SSc patients with signs of pulmonary fibrosis on chest radiography HRCT was performed. No patients had diabetes mellitus or renal failure.

Clinical and laboratory data recorded at the time of serum collection included pulmonary and renal function tests, renal sonography as well as erythrocyte sedimentation rate (ESR), haemoglobin, platelet counts, urine analysis, serum creatinine and urinary protein excretion.

Antinuclear antibodies (ANA) were assessed using commercial enzyme-linked immunosorbent assay (ELISA) kits (Cogent Diagnostics Autostat, Penicuik, UK). Antibodies against topoisomerase-I (anti-TOPO-I, anti-Scl-70) were measured using commercial ELISA kits (Trinity Biotech, Jamestown, N.Y., USA).

Serum specimen preparation

Blood samples were clotted for 30 min and next centrifuged for 10 min at 1000 g. Serum aliquots were frozen at −80°C immediately after collection.

Enzyme-linked immunoassays (ELISA)

The serum concentrations of vascular cell adhesion molecule-1 (sVCAM-1) and E-selectin (sE-selectin) were measured using commercial ELISA kits (Bender MedSystems, Vienna, Austria). Levels of vascular endothelial growth factor (VEGF) were assessed by an ELISA kit from R&D Systems (Wiesbaden-Nordenstadt, Germany). Levels of ET-1 were assessed by an ELISA kit from Immuno-Biological Laboratories (Naka, Fujioka-Shi, Gunma, Japan). Assays were carried out according to the manufacturer’s instructions.

Statistical analysis

Clinical data and ESR, sVCAM-1, VEGF and ET-1 values were compared using the unpaired Student t-test or Mann-Whitney U test as appropriate. The probability of differences in frequency distributions was determined by a chi-square test or Fisher’s exact test; p values lower than 0.05 were considered statistically significant.

Results

Fourteen patients had the diffuse form of SSc (dSSc) and 17 had its limited form (lSSc), as assessed by location and extent of skin involved. All patients complained of Raynaud’s phenomenon.

The characteristics of both SSc groups with and without systemic involvement are shown in Table 1. There were no significant differences in age and disease duration between the two groups of SSc patients with different clinical features. The diffuse form of SSc (dSSc), digital pitting scars, telangiectasia, the positive ANA and anti-topoisomerase-I antibodies were observed more frequently in patients with systemic manifestation compared with the group without internal organ involvement.
Table 1

Patient characteristics. Data presented as means±SD. SD standard deviation, SSc systemic sclerosis, NS not significant, ESR, erythrocyte sedimentation rate, ANA antinuclear antibodies, TOPO I anti-topoisomerase I antibodies

SSc patients without systemic involvement

SSc patients with systemic involvement

p<

Number of patients

15

16

NS

Age (years)

51.5±11.6

58.6±8.0

NS

Disease duration (years)

6.1±4.7

9.4±6.9

NS

Diffuse SSc/limited SSc

2/13

12/4

0.01

Patients with digital pitting scars (n, %)

4 (26.7)

9 (56.3)

NS

Patients with telangiectasia (n, %)

5 (33.3)

10 (62.5)

NS

ESR (mm/1st h)

27.1±20.4

53.9±43.1

0.05

ANA positive (n, %)

5 (33.3)

14 (87.5)

0.01

TOPO I positive (n, %)

1 (6.7)

6 (37.5)

0.05

Prednisolone <5 mg/day (n, %)

4 (26.7)

5 (31.3)

NS

Pentoxifylline (n, %)

7 (46.7)

13 (81.3)

NS

Calcium antagonists (n, %)

0 (0)

2 (12.5)

NS

Data concerning the patients’ treatment are shown in Table 1. Nine patients were treated with prednisolone at low dosage (<5 mg/day), 20 patients were receiving vasodilators and 7 patients were without medication at the time of the study. No patient had received immunosuppressant drugs at the time of sampling. Two patients were under calcium antagonist treatment, due to Raynaud’s disease. In these patients, before blood sampling, an adequate pharmacological washout period was observed.

Serum levels of sVCAM-1 (Fig. 1), sE-selectin (Fig. 2), VEGF (Fig. 3) and ET-1 (Fig. 4) were measured in 31 SSc patients, including 16 cases with systemic involvement, 15 cases without any evidence of internal organ manifestation and in 30 healthy subjects (Table 2). In all SSc patients the concentrations of sVCAM-1, sE-selectin, VEGF and ET-1 were raised compared with age-matched healthy controls (p<0.001 in all cases).
Fig. 1

Serum concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1) in patients studied. Assessment was based on ELISA technique. Data presented as means±SD

Fig. 2

Serum concentrations of soluble E-selectin (sE-selectin). Assessment was based on ELISA technique. Data presented as means±SD

Fig. 3

Serum concentrations of soluble vascular endothelial growth factor (VEGF). Assessment was based on ELISA technique. Data presented as means±SD

Fig. 4

Serum concentrations of endothelin-1 (ET-1). Assessment was based on ELISA technique. Data presented as means±SD

Table 2

Serum concentrations of soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in healthy controls and systemic sclerosis patients without and with systemic involvement. Data presented as means±SD. Significances of the differences between groups were described in the “Results” section and in figures. SD standard deviation, SSc systemic sclerosis, sVCAM-1 soluble vascular cell adhesion molecule-1, sE-selectin soluble E-selectin, VEGF vascular endothelial growth factor, ET-1 endothelin-1

Healthy controls

All SSc patients

SSc patients without systemic involvement

SSc patients with systemic involvement

Number of patients

30

31

15

16

sVCAM-1 (ng/ml)

528.6±172.9

682.6±172.8

617.8±141.2

743.4±181.7

sE-selectin (ng/ml)

34.7±12.1

47.3±13.4

41.7±8.9

52.4±15.1

VEGF (pg/ml)

172.4±78.2

273.2±145.8

213.3±106.6

329.4±157.9

ET-1 (pg/ml)

4.28±2.63

17.33±8.75

13.10±7.24

21.29±8.34

Comparison between both SSc groups with and without internal organ involvement showed significantly higher levels of sVCAM-1, sE-selectin, VEGF (p<0.05 in all cases) and ET-1 (p<0.01) in the sera of patients with systemic manifestation. Although the mean serum levels of sVCAM-1, sE-selectin, VEGF and ET-1 were higher in both SSc subgroups than in the control group, a significant difference between SSc patients without systemic involvement and controls could be shown only in the case of ET-1 concentration (p<0.001).

Discussion

Vascular damage resulting in endothelial cell injury is a key element in the pathogenesis of SSc. Since vascular dysfunction in SSc precedes the development of fibrosis, endothelial cell injuries have been implicated in the pathophysiology of fibrosis [1]. Overexpression of cell adhesion molecules, endothelial growth factors and the proliferation of new blood vessels may play an important role in internal organ damage in the disease process [3, 7, 10].

Renal, myocardial and pulmonary involvement may remain clinically silent for a long time and cause substantial morbidity and mortality in SSc. Recently, many studies have concentrated on the role of angiogenesis and endothelium in the pathogenesis of some extra-articular manifestations in rheumatic diseases [16, 17, 18]. However, few data exist on the relationship between the immunological alterations and internal organ involvement in SSc.

The importance of cell adhesion molecules in the pathogenesis of SSc is confirmed by the overexpression of these molecules on endothelial cells and fibroblasts in lesional skin [19]. Moreover, the elevation of soluble forms of cell adhesion molecules (sCAMs) in active disease stages of scleroderma was associated with enhanced in situ expression of ICAM-1, VCAM-1, P-selectin and, to a lesser degree, E-selectin on endothelial cells [19]. Overexpression of E-selectin at the mRNA and protein levels was also found in salivary endothelial cells of patients with SSc [20].

In a previous study, we demonstrated significantly elevated serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), sVCAM-1, sE-selectin and VEGF in RA patients with distinct variants of rheumatoid synovitis [21] and sICAM-1 in patients with rheumatoid vasculitis [22] and in connective tissue diseases (CTD) with vasculitis [23].

In the present study, serum sVCAM-1 and sE-selectin concentrations were significantly raised in all SSc patients. Furthermore, both adhesion molecules reached the highest levels in patients with systemic organ involvement, distinguishing them from those without internal organ manifestation. Several studies have demonstrated increased sVCAM-1 and sE-selectin levels in serum of SSc patients compared with the healthy controls [24, 25]. Moreover, a significant correlation between sVCAM-1 and sE-selectin concentrations and the extent of the skin involvement in SSc patients has been observed [24], although some reports revealed that serum sVCAM-1 elevation in SSc patients was not significant [11]. However, in the same study, increased sE-selectin levels in patients with RA, SSc and vasculitis was found [11]. Other investigators suggest that a decrease in serum sVCAM and sE-selectin levels was associated with an improvement of renal function and softening of the skin in the majority of SSc patients [26]. Other investigators postulated that E-selectin and sVCAM-1 may be important in triggering angiogenesis in the initial stages of RA [27]. Raised sVCAM-1 and sE-selectin, especially in SSc patients with systemic organ involvement, could be an indicator of endothelial cell injury and/or activation. Moreover, some reports suggest that circulating levels of E-selectin could be a useful marker in monitoring the disease activity and the effects of therapy in SSc [28]. In our previous study, serum concentrations of sICAM-1, sVCAM-1 and sE-selectin correlated with clinical activity of the disease and sVCAM-1 was associated with distinct histopathological manifestations of RA [21]. Taken together, all these findings suggest that sVCAM-1 and sE-selectin may be useful markers of systemic vascular inflammation in SSc patients.

Recently, vascular endothelial growth factor (VEGF) as a potent mediator of endothelial proliferation, angiogenesis, and capillary hyperpermeability has attracted much attention [8, 29]. It is postulated that VEGF might be involved in the pathogenesis of RA [30]. Several studies have demonstrated higher VEGF concentrations in serum in RA patients than in controls [7, 8 ,9]. Moreover, our previous study showed that the increased VEGF serum level is related to RA activity and associated with histological manifestation of the disease [21]. In the present study, the serum levels of VEGF were significantly higher in all patients with SSc than in controls. Furthermore, the highest VEGF concentration was found in patients with organ involvement when compared to those without systemic manifestation of the disease. Although in some studies serum concentration of VEGF was increased in SSc patients relative to healthy controls, those differences were not significant [7, 8]. However, the authors reported that VEGF serum levels in the patients with dSSc were significantly higher than in the normal controls [7]. In our study, most patients with systemic organ involvement represent the diffuse form of SSc. Moreover, lung fibrosis was the most frequent systemic organ involvement observed in this study. These findings confirm the observations of other authors [7] that an increased VEGF level may be correlated with the frequency of lung fibrosis. It has been demonstrated that an exuberant endothelial cell proliferation is observed in patients with pulmonary hypertension associated with SSc [31]. Therefore, the elevated VEGF levels in SSc patients with pulmonary involvement suggest that VEGF plays an important role in the development of lung fibrosis.

Endothelin-1 (ET-1) as the most potent endothelium-derived vasoconstrictor substance has been implicated in the pathogenesis of multiple vascular diseases [11]. It is postulated that overexpression of ET-1 is associated with mitogenic, fibrotic and inflammatory activity [32]. It was shown that keratinocyte-derived ET-1 plays an important role in the pathogenesis of the hyperpigmentation of the skin in severe cases of SSc [33]. Several studies have demonstrated increased ET-1 concentrations in SSc patients [11, 34]. Moreover, ET-1 levels were found to correlate with skin fibrosis and duration of disease in patients with SSc [34]. However, in another study, circulating ET-1 levels were not related to the presence of interstitial lung disease [11]. In the present study, we observed the serum ET-1 concentrations to be higher in all SSc patients in comparisons with controls. Furthermore, the SSc patients with internal organ involvement showed significantly higher levels of ET-1 compared with those without any evidence of systemic manifestations. These findings strengthen the concept that ET-1 may be important in the pathogenesis of vascular manifestation in SSc.

In our study, we demonstrated significantly elevated levels of sVCAM-1, sE-selectin, VEGF and ET-1 in SSc serum compared with healthy controls. Concentrations of these molecules were especially elevated in patients with systemic organ involvement distinguishing them from those without signs of systemic manifestation of the disease. These results suggest that the serum levels of sVCAM-1, sE-selectin, VEGF and ET-1 may reflect the extent of internal involvement in SSc patients and point to a pathogenic role of these molecules in systemic manifestation of the disease.

Further studies are needed to document the potential role of the immunopathological mechanisms of internal organ manifestation in SSc. A clearer understanding of these processes may be crucial for early detection, monitoring and prognosis of the disease.

Take home message

Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) may reflect the extent of internal organ involvement in systemic sclerosis patients and point to a pathogenic role of these molecules in systemic manifestation of the disease.

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Copyright information

© Clinical Rheumatology 2004

Authors and Affiliations

  • Anna Kuryliszyn-Moskal
    • 1
  • Piotr Adrian Klimiuk
    • 1
  • Stanislaw Sierakowski
    • 1
  1. 1.Department of Rheumatology and Internal DiseasesMedical University of BialystokBialystokPoland

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