Expression pattern of VEGFR-1, -2, -3 and D2-40 protein in the skin of patients with systemic sclerosis.
ABSTRACT The earliest clinical symptoms of systemic sclerosis (SSc) relate to disturbances in the peripheral vascular system. However, detailed examination of the microcirculation including the lymphatics in the skin of patients with SSc has not been reported. The aim of our study was to examine the expression patterns of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3 and the lymphatic endothelial cell marker D2-40 in the skin of SSc patients. Skin biopsy specimens from nine patients with SSc were analysed by immunohistochemistry using antibodies against VEGFR-1, VEGFR-2, VEGFR-3 and D2-40 protein. The lumen area of lymphatic vessels was measured. The data were statistically analysed using the Mann-Whitney U test, Wilcoxon signed-ranks or Spearman's rank correlation coefficient method. The intensity of VEGFR-2 and VEGFR-3 staining in the skin of patients with SSc was significantly higher than that in healthy controls. The lumen area of lymphatic vessels in the skin of patients with SSc was significantly larger than that in healthy controls. This study details the expression of VEGFR and D2-40 in the skin of patients with SSc, and highlights a possible role of microcirculatory dysfunction in the pathogenesis of systemic sclerosis.
- SourceAvailable from: Georges Uzan[Show abstract] [Hide abstract]
ABSTRACT: To assess angiogenesis and explore the expression and regulation of vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR-1), and VEGFR-2, the leading mediators of angiogenesis, in SSc patients and controls. Late-outgrowth endothelial progenitor cells (EPCs), isolated from the peripheral blood of systemic sclerosis (SSc) patients and controls, and human umbilical vein endothelial cells (HUVECs) were assessed under normal and hypoxic conditions. Genomic background was evaluated in a large case-control study (including 659 patients with SSc and 511 controls) using tag single-nucleotide polymorphisms on VEGFR1 and VEGFR2 genes. EPCs from SSc patients had the phenotype of genuine endothelial cells and displayed in vitro angiogenic properties similar to those of HUVECs and control EPCs under basal conditions, as determined by flow cytometry, tube formation, and migration assay. However, after 6 hours of hypoxic exposure, EPCs from SSc patients exhibited lower induced expression of VEGFR-1 at the messenger RNA and protein levels, but similar VEGF and VEGFR-2 expression, compared with HUVECs or EPCs from healthy controls. There was no evidence of defective expression of hypoxia-inducible factor 1alpha. These results were supported by the lower serum levels of soluble VEGFR-1 found in SSc patients (n = 187) compared with healthy controls (n = 48) (mean +/- SD 163.7 +/- 98.5 versus 210.4 +/- 109.5 pg/ml; P = 0.0042). These abnormalities did not seem to be related to genomic background. Our findings shed new light on the possible role of VEGFR-1 in the main vascular disturbances that occur in SSc and lead to more severe disease.Arthritis & Rheumatology 12/2008; 58(11):3550-61. · 7.87 Impact Factor
- Seminars in Arthritis and Rheumatism 06/1975; 4(4):351-68. · 3.63 Impact Factor
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ABSTRACT: Systemic sclerosis (SSc) is a disorder characterized by vascular damage and fibrosis of the skin and internal organs. Despite marked tissue hypoxia, there is no evidence of compensatory angiogenesis. The ability of mesenchymal stem cells (MSCs) to differentiate into endothelial cells was recently demonstrated. The aim of this study was to determine whether impaired differentiation of MSCs into endothelial cells in SSc might contribute to disease pathogenesis by decreasing endothelial repair. MSCs obtained from 7 SSc patients and 15 healthy controls were characterized. The number of colony-forming unit-fibroblastoid colonies was determined. After culture in endothelial-specific medium, the endothelial-like MSC (EL-MSC) phenotype was assessed according to the surface expression of vascular endothelial growth factor receptors (VEGFRs). Senescence, chemoinvasion, and capillary morphogenesis studies were also performed. MSCs from SSc patients displayed the same phenotype and clonogenic activity as those from controls. In SSc MSCs, a decreased percentage of VEGFR-2+, CXCR4+, VEGFR-2+/CXCR4+ cells and early senescence was detected. After culturing, SSc EL-MSCs showed increased expression of VEGFR-1, VEGFR-2, and CXCR4, did not express CD31 or annexin V, and showed significantly decreased migration after specific stimuli. Moreover, the addition of VEGF and stromal cell-derived factor 1 to cultured SSc EL-MSCs increased their angiogenic potential less than that in controls. Our data strongly suggest that endothelial repair may be affected in SSc. The possibility that endothelial progenitor cells could be used to increase vessel growth in chronic ischemic tissues may open up new avenues in the treatment of vascular damage caused by SSc.Arthritis & Rheumatology 07/2007; 56(6):1994-2004. · 7.87 Impact Factor